2023 - The Impact - Loneliness - Alzheimer

Frontiers in Neuroendocrinology 69 (2023) 101061
Contents lists available at ScienceDirect
Frontiers in Neuroendocrinology
journal homepage: www.elsevier.com/locate/yfrne
Review article
The impact of loneliness and social isolation on the development of

cognitive decline and Alzheimer’s Disease
Yi Ren c, d, e, Aisouda Savadlou a, e, f, 1, Soobin Park a, e, f, 1, Paul Siska a, e, f, Jonathan R. Epp c, d, e,
Derya Sargin a, b, e, f, *
a
Department of Psychology, University of Calgary, Canada
b
Department of Physiology & Pharmacology, University of Calgary, Canada
c
Department of Cell Biology and Anatomy, University of Calgary, Canada
d
Cumming School of Medicine, University of Calgary, Canada
e
Hotchkiss Brain Institute, University of Calgary, Canada
f
Alberta Children’s Hospital Research Institute, University of Calgary, Canada
A R T I C L E I N F O A B S T R A C T
Keywords: Alzheimer’s Disease (AD) is the leading cause of dementia, observed at a higher incidence in women compared
Alzheimer’s Disease with men. Treatments aimed at improving pathology in AD remain ineffective to stop disease progression. This
Loneliness makes the detection of the early intervention strategies to reduce future disease risk extremely important.
Social isolation
Isolation and loneliness have been identified among the major risk factors for AD. The increasing prevalence of
Risk factors
both loneliness and AD emphasizes the urgent need to understand this association to inform treatment. Here we
Cognition
Sex differences present a comprehensive review of both clinical and preclinical studies that investigated loneliness and social
isolation as risk factors for AD. We discuss that understanding the mechanisms of how loneliness exacerbates
cognitive impairment and AD with a focus on sex differences will shed the light for the underlying mechanisms
regarding loneliness as a risk factor for AD and to develop effective prevention or treatment strategies.
1. Introduction subjective perception of an unfulfilled level of social contact and feelings

of alienation (Hawthorne, 2008; Sundström et al., 2020). Loneliness, or
Humans are innately social beings, dependent on and motivated by perceived social isolation, is experienced when an individual’s social
social relationships from infancy to old age (Hay et al., 2004; Sutcliffe expectations are not met, and social interactions are perceived as less
et al., 2012). Through social interactions, numerous fundamental mo fulfilling (Cacioppo and Hawkley, 2009). Hence, a person does not have
tives such as reproduction, the need for self-protection, belonging and to be socially isolated to feel lonely.
status are met (Baumeister and Leary, 1995; Neel et al., 2016). The In humans, both social isolation and loneliness have been associated
importance of social interaction is emphasized by studies that demon with negative physical health impacts, such as increased blood pressure,
strate social isolation and loneliness as risk factors for negative health stress response, and risk of cardiovascular disease (Hawkley and
outcomes and increased mortality (Golaszewski et al., 2022; Holt- Cacioppo, 2010; Steptoe et al., 2013) with an overall increased risk for
Lunstad, 2021; Holt-Lunstad et al., 2015; Valtorta et al., 2016). Social mortality at comparable odds ratios (reviewed in (Holt-Lunstad et al.,
isolation and loneliness are often used interchangeably; however, these 2015; Leigh-Hunt et al., 2017)). Loneliness has also been reported to
two terms are defined and measured differently. Social isolation occurs have negative impacts on mental health (Cacioppo et al., 2010), with
when individuals lack adequate social support, communication and increased depressive and anxiety symptoms (Beutel et al., 2017;
engagement with others (McPherson et al., 2006). Social isolation has an Cacioppo et al., 2006; Holvast et al., 2015), sleep irregularities (Hawkley
objective component that is measurable through social network size, et al., 2010), and cognitive decline (Canli et al., 2018; Shankar et al.,
marital status, living arrangement, among other factors (Cornwell and 2013; Wilson et al., 2007). While several studies have used the term
Waite, 2009; Hawthorne, 2008). In contrast, loneliness is described as a ‘social isolation’ to encompass both loneliness and a lack of social
* Corresponding author at: University of Calgary, 2500 University Ave Dr NW T2N 1N4, Calgary, AB, Canada.
E-mail address: derya.sargin@ucalgary.ca (D. Sargin).
1
These authors contributed equally.
https://doi.org/10.1016/j.yfrne.2023.101061
Received 29 November 2022; Received in revised form 19 January 2023; Accepted 3 February 2023
Available online 8 February 2023
0091-3022/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Y. Ren et al. Frontiers in Neuroendocrinology 69 (2023) 101061
contact (Teo et al., 2013), those comparing objective and subjective 2. Social isolation/loneliness and AD in human studies
isolation have found a stronger correlation between perceived isolation
(or loneliness) and depression ((Cho et al., 2019; Taylor et al., 2018); 2.1. Social isolation and loneliness as risk factors for cognitive decline
reviewed in (Santini et al., 2015)). Overall, prolonged social isolation
and particularly loneliness are a major source of psychosocial stress that Mild cognitive impairment (MCI) is the transitional phase between
increases the prevalence of diseases associated with neuropsychological cognitive decline caused by normal ageing and diagnosis of AD de
dysfunction. When compared directly, both loneliness and social isola mentia (Petersen, 2004). MCI is considered to be a pathological condi
tion were found to have strong associations with lower cognition, tion characterized by manifestation of cognitive deficits that cannot be
evident across multiple cognitive tasks and domains (Lara et al., 2019). solely attributed to the ageing process. Despite the universal recognition
In contrast, while some studies reported a significant association be of MCI as a diagnostic entity, there has been considerable heterogeneity
tween social isolation and poor cognition or dementia (Elovainio et al., in the applied diagnostic criteria across different studies. Estimates for
2022; Penninkilampi et al., 2018; Shen et al., 2022; Yu et al., 2021), the risk for conversion from MCI to dementia have also substantially
others found a stronger association with loneliness and dementia (Hol varied among studies with subjects recruited from clinical settings
werda et al., 2014; Rafnsson et al., 2020). The discrepancy has been compared to those with community-dwelling volunteers (Bruscoli and
attributed to an inconsistency in the inclusion of all risk factors and/or Lovestone, 2004). Regardless of the variabilities between studies, the
the heterogeneity of cognitive tests used in the analyses (Shen et al., mean annual conversion rate of 10 % is five times more than the inci
2022). These findings highlight the importance of studying social dence of dementia in age-matched controls. These studies supported that
isolation and loneliness in tandem, despite the low to moderate corre MCI diagnosis is indeed beneficial for detecting patients at high risk of
lation between the two entities (Coyle and Dugan, 2012; Perissinotto dementia and AD.
and Covinsky, 2014). A significant amount of research has focused on exploring early
Elderly people are particularly susceptible to becoming isolated, manifestations of AD that can be used to assess asymptomatic patients
with loneliness affecting 12 % to 40 % of those 65 years old or older (Petersen and Jack, 2009). The longitudinal Zaragoza Dementia
(Creecy et al., 1985). The incidence of cognitive decline, memory Depression Project (ZARADEMP), with 4,803 participants over the age
impairment and/or dementia is higher among seniors who report feel of 55 conducted the first comprehensive analysis of the association be
ings of loneliness. These studies suggest that people at an older age tween BPSD at baseline and the occurrence of MCI and AD-related de
become more susceptible to developing dementia and Alzheimer’s Dis mentia (Lobo et al., 2005, 2008). The authors detected a distinct
ease (AD) if they have been subjected to chronic loneliness (d’Oleire psychopathological profile in association with MCI and AD, suggesting
Uquillas et al., 2018; Wilson et al., 2007). In contrast, socially integrated that MCI may represent a rather heterogeneous condition than a simple
individuals appear to be more resilient to the processes that impact early manifestation of dementia. This has also been the first report of a
neurobiological function. As a major risk factor for AD-related dementia, significant association between psychopathological factors such as
the pathophysiological mechanisms of how loneliness contributes to AD loneliness and MCI. Others have since explored the link between
should be further investigated to understand and prevent disease cognitive decline and social isolation/loneliness in the elderly popula
progression. tion. Many of these studies have identified that loneliness and/or social
AD is the most common form of dementia impacting 10 % of in isolation are risk factors for and are associated with greater cognitive
dividuals over the age of 65 and 33 % of those over 85 (Newcombe et al., decline (reviewed in Bhatti and Haq, 2017; Boss et al., 2015; Cacioppo
2018). AD is characterized by amyloid-beta (Aβ) peptide containing and Hawkley, 2009) (Table 1). Numerous longitudinal studies of
senile plaques, hyperphosphorylated tau protein which forms neurofi different methodological designs and durations have independently
brillary tangles, and neuronal degeneration (Glenner and Wong, 1984; established a significant link between loneliness or social isolation at
Grundke-Iqbal et al., 1986; Mirra et al., 1993). Patients with AD present baseline and poorer cognitive function at follow up. Some of these
with memory loss, confusion and cognitive impairment. In addition to determined the impact of loneliness and/or social isolation on distinct
cognitive symptoms, most AD patients also display behavioral and cognitive domains. Accordingly, isolation and loneliness have been
psychological symptoms of dementia (BPSD) such as aggression, anxi associated with impaired verbal memory at baseline and when assessed
ety, apathy, mood swings, hallucinations and delusions (Li et al., 2014; four years later, with an unexpected greater effect of isolation alone
Tariot et al., 1995). Familial AD mutations in the amyloid precursor (Shankar et al., 2013). Others similarly detected a significant decline in
protein (APP) have been discovered and are commonly used to generate future verbal memory and fluency in lonely individuals over a decade
rodent models for AD. However, the majority of AD cases, which are (Luchetti et al., 2020; Yin et al., 2019). A number of longitudinal studies
referred to as sporadic, do not stem from these mutations. Sporadic performed an analysis of global cognitive function based on tests such as
causes of AD are unknown yet, environmental and physiological risk Mini-Mental State Examination (MMSE) (Wang et al., 2020; Zhong et al.,
factors can contribute to AD development and progression (Flicker, 2017), and the Cambridge Cognitive Examination (CAMCOG) (Evans
2010; Stozická et al., 2007) further supporting the importance of un et al., 2019). These analyses detected a significant impairment in
derstanding the risk factors for early intervention. Since AD is being attention, learning and memory, language, orientation, comprehension
considered as a pathologic continuum, the preclinical stage of AD before and expression years later in lonely subjects compared to those who
the onset of evident cognitive impairment is a critical window for reported not feeling lonely at baseline (Evans et al., 2019; Freak-Poli
studying the epidemiology of the disease and for diagnosis and et al., 2022; Giné-Garriga et al., 2021; Zhong et al., 2017) but also see
treatment. (Pugh et al., 2021; Wang et al., 2020; Yu et al., 2021).
In this review, we outline the effect of loneliness and social isolation The relationship between loneliness and global cognition scores or
on AD development and the onset of AD symptoms in humans and an specific cognitive domains has further been explored in a number of
imal models, respectively. Clinical studies on loneliness often include cross-sectional studies conducted in healthy, older subjects. Self-
subjective measures of cognitive and behavioral symptoms and potential reported loneliness was associated with impaired global cognition
confounds, as well as measures used to analyze the physiological fea based on MMSE scores, specifically with reduced psychomotor pro
tures of AD in lonely people. Animal studies using AD genetic models cessing speed and visual memory (O’Luanaigh et al., 2012). Although
assess pathological and behavioral features of AD after social isolation. loneliness did not directly affect cognitive performance in each cross-
In reviewing this literature, we aim to suggest how loneliness in humans sectional study, its negative impact on executive function remained
may act as a risk factor for AD and as a potential target for early significant (Montoliu et al., 2019). Altogether these data showed that
intervention. loneliness negatively impacts various cognitive domains, notably
memory, in the elderly population. These deficits are also some of the
2
Table 1
Loneliness and/or social network as a risk factor for cognitive decline, dementia or Alzheimer’s Disease.
Number of subjects Study Design Inclusion Assessment of Assessment of Adjusted factors Results Original
loneliness or cognition Publication
social networks
Total: 1203 Longitudinal Age: >75 (mean Obtained by Diagnosis of Age, Sex, Edu, Being single and living Fratiglioni
F: 897 population-based 81.5); personal dementia Depr, BC (MMSE alone doubled the risk et al. (2000)
M: 306 study (The No dementia at interview: according to the score), PA, CVD, of developing
Kungsholmen baseline; marital status, DSM-III-R high blood dementia.
Project), followed- good cognition living Incidence rate: pressure A limited SN increased
up to 3 years (MMSE > 23); arrangement, F 56.5 %, M the risk (60 %).
lived at home. presence of 37.0 % Dementia risk did not
children, increase if infrequent
frequency of contacts were
contacts, satisfying.
satisfaction with
relationships,
close social ties
Total: 823 Longitudinal Age: 80.7 ± 7.1 Modified de Jong- Global cognitive Age, Sex, Edu, Loneliness doubled the Wilson et al.
F: 75.7 % clinicopathologic Gierveld tests (MMSE, Depr, SA, SN, PA, risk for the (2007)
cohort study, Loneliness Scale memory, speed, Inc, Eth, Race, PC development of AD-
followed-up to 4 visuospatial like dementia.
years ability) No association between
loneliness and AD
pathology.
Baseline: Wave I: Baseline Age: >55; Assessed as a part GMS, DSM, Age, Sex, Edu Loneliness was among Lobo et al.
F: 2771 cross-sectional; Wave I: No dementia, of GMS MMSE, Lawton the psychopathological (2008)
M:2032 Wave II: normal cognition. & Brody Scale factors associated with
Follow-up: Longitudinal(The Wave II: Abnormal MCI.
F:1792 ZARADEMP score in MMSE and
M:1452 Project), followed- GMS (memory loss),
up to 2 years normal scores in
Lawton & Brody and
Katz’ Index.
Total: 2089 Longitudinal, Age ≥ 65 Self-report of Diagnosis of Sex, Edu, Depr, BC Satisfaction in social Amieva
F:1251 epidemiological (mean 73.7) marital status, dementia (MMSE score), PC, relations: 23 % reduced et al. (2010)
M: 838 population-based No dementia at size and nature of confirmed PA risk of dementia.
study (PAQUID), baseline, 1 and 3 year social network, through the Perception of
followed-up to 15 follow-up composition, following reciprocity (receiving
years satisfaction with criteria: more than giving):
relationships, NINCDS- reduced risk of
perception of ADRDA (AD), dementia (55 %) and
being understood, NINDS-AIREN AD (53 %).
and reciprocity in (VaD)
social interactions standardized
clinical criteria
(fronto-
temporal
dementia, Lewy
body disease),
history taking
(Parkinson
dementia)
Total: 466 Cross-sectional Age: 75.45 ± 6.1, CES-D loneliness MMSE, NART-2, Age, Sex, Edu, SC, Association between O’Luanaigh
F: 258 study MMSE > 23 question, SN WAIS III digit Mar, Depr, SN, pre- loneliness and lower et al. (2012)
M: 208 using WSNT symbol coding, morbid IQ, BC global cognitive
FAS test and measures, in particular
Animal fluency, with impaired
WMS III processing speed and
visual memory.
Total: 6034 Longitudinal study Age ≥ 50 Revised 3-item Verbal fluency, Age, Sex, Edu, Mar, Association between Shankar
M: 45.3 % (ELSA), followed- (mean 65.6) UCLA Loneliness immediate and adjusted wealth, isolation/loneliness et al. (2013)
up to 4 years Scale delayed recall Emp, CVD, Depr, and decreased
PA, DM, Smo cognitive performance
at baseline (worse
verbal fluency, delayed
and immediate recall)
and at follow-up
(worse delayed and
immediate recall)
Although isolation was
not significantly
associated with sex,
loneliness
was higher among
women.
(continued on next page)
3
Table 1 (continued )
social networks
Total: 2173 Longitudinal, Age > 65, Social isolation MMSE Edu, Depr, PC, BC Association between Holwerda
F:1372 population-based no dementia at and loneliness (cognition), (MMSE score), PC, loneliness and et al. (2014)
M:801 cohort study baseline each assessed GMS AGECAT Alc, Smo, incidence dementia.
(AMSTEL), through one (dementia generalized No association between
followed-up to 3 question diagnosis) anxiety social isolation and
years dementia risk.
No differences between
men and women in
developing dementia.
Total: 1715 Longitudinal, Age ≥ 65 Self-reports on Diagnosis of all- Age, Sex, Edu, Higher value on Sörman
F: 958 population-based, (mean 72.20) living status, cause dementia Depr, BC (MMSE relationship index was et al. (2015)
M: 757 prospective study having a close and AD score), PC, Alc, associated with
(Betula), followed- friend, contact according to the Smo, general stress reduced risk of all-
up to 16 years frequency and DSM-IV, MMSE cause dementia and
satisfaction AD.
Among those who
developed all-cause
dementia or AD, a
higher proportion were
women and a higher
proportion lived alone.
Total: 8382 Longitudinal study Age ≥ 65 Loneliness 10-word list Age, sex, Race, Loneliness at baseline Donovan
M: 40 % (Harvard Aging (mean 73.2) question from the from TICS, Edu, Inc, Wealth, was associated with a et al. (2017)
Brain Study), 8 item CES-D IQCODE for PC, Depr 20 % higher decline in
followed-up to 12 impaired cognition over 10
years participants years.
Total: 779 Cross-sectional Age ≥ 70 Self-reported Diagnosis of Sex, Age, Edu, Eth, Living alone and Poey et al.
F: 452 study family network dementia by Race, Depr, PC, PA, loneliness were (2017)
M: 327 (ADAMS) size, social healthcare BC (TICS, associated with a
engagement, practitioner. shortened greater risk for non-AD
marital status, APOE-ε4 allele IQCODE) dementia and cognitive
living presence by difficulty, respectively.
arrangements, buccal swab. Presence of the ε4
perceived allele and less social
availability of engagement were
social support, independently
and loneliness associated with
(single item from increased risk of AD.
CES-D 8)
Total: 1601 Longitudinal study Age ≥ 55 Self-reports on MMSE, CDR, Age, Sex, Edu, Being married and Rawtaer
F: 1033 (SLAS), followed- (mean 64.9), living MCI and Depr, Eth, PC, SA, satisfied with life were et al. (2017)
M: 568 up to 8 years no dementia at arrangement and dementia PA, Alc, Smo, associated with lower
baseline marital status, diagnosis APOE-ε4 risk of MCI-dementia.
loneliness (3- according to Living alone or
point Likert scale Peterson’s loneliness was not a
question), life criteria and predictor of incident
satisfaction DSM-IV MCI-dementia.
No gender differences
in the effect of marital
status on incident MCI-
dementia.
Total: 14,199 for Longitudinal study Age ≥ 65 Single question Chinese Age, Sex, Edu, PA, Loneliness and Zhong et al.
analyses, (CLHLS), followed- (mean 85) Modified MMSE Smo, Mar, Living isolation at baseline (2017)
M: 44.26 % up to 9 years arrangement were associated with
poorer future cognitive
performance.
Total: 93 Cross-sectional Age ≥ 55 De Jong Gierveld MMSE Age, Sex, Depr, SN, In subjects with AD, Balouch
F: 51 study (mean 82.61); Loneliness Scale, loneliness larger SN (friends but et al. (2019)
M: 42 diagnosis of AD LSNS-6 not family) was
6–24 months before associated with higher
enrolment; global cognition.
standardized MMSE No association between
score of 12–26 loneliness and global
cognition.
Total: 345 Longitudinal Age: 75.1 ± 7.3 Self-reports on MMSE, CDR, Age, Sex, Edu, Subjects with MCI who Grande et al.
F: 56 % clinical-based living situation word recall Depr (use of lived alone had 50 % (2018)
study, followed-up and civil status (immediate, antidepressants), higher risk of
to 5 years delayed), PC developing dementia
language, and were diagnosed
attention and about 1 year earlier
executive than those who lived
function, with others.
visuospatial
ability.
4
social networks
Dementia
diagnosis
according to
DSM-IV.
Total: 7867 Longitudinal Age ≥ 65 Loneliness Diagnosis of Age, Sex, SI, Edu, Loneliness increased Zhou et al.
F: 4316 cohort study (mean 83.09), assessed through dementia by PA, BC (MMSE the risk of dementia. (2018)
M: 3551 (CLHLS), followed- no dementia at single question, healthcare score), PC, Alc, Significant interaction
up to 3 years baseline self-reports of practitioner Smo, rural, between loneliness and
living status, institution, nut and gender.
social support milk intake
Baseline: Longitudinal study Age ≥ 65 LSNS-6; De Jong CAMCOG, Baseline CAMCOG, No association between Evans et al.
F: 1112 (CFAS-Wales), (mean 73.46), Gierveld cognitive Age, Sex, Edu, SI, living alone and (2019)
M:1085 followed-up to 2 no cognitive Loneliness Scale reserve loneliness,SA, Mar, cognitive function.
Follow-up: years impairment or measured by ADL impairment Social isolation
F: 751 depression at baseline level of predicted poor
M: 747 education, cognitive function at
cognitive baseline and follow-up.
activity and Loneliness predicted
occupational poor cognitive function
complexity only at baseline.
Total: 86 Cross-sectional Age: 60–80 Revised UCLA MMSE, TMT-A Age, Sex, Mar, Loneliness had a direct Montoliu
F: 45 study (mean 67.44) Loneliness Scale and TMT-B, LNS Depr, Edu impact on bedtime et al. (2019)
M: 41 lack of drug/ from WMS III, cortisol levels and an
medication use, RBMT indirect impact on
neuropsychological (immediate and cognitive function.
disease, stressful and/ delayed) No sex differences.
or important life
events in the past year
Baseline: 8780 Longitudinal study Age ≥ 50 Revised UCLA Memory (10 Age, Sex, Edu, Loneliness was Yin et al.
M: 44.6 % (ELSA), followed- (mean 65.3), loneliness scale words, recall), Wealth, PC, Depr associated with poorer (2019)
Total for analysis: up to 10 years no dementia or stroke verbal fluency cognitive function at
5885 at baseline baseline and with a
stronger cognitive
decline over time.
Total: 6654 Longitudinal study Age ≥ 65 Loneliness − 3 Modified TICS; Age, Sex, Edu, PC, Loneliness and cynical Griffin et al.
F: 6026 (HRS), followed-up (mean 72.57) item UCLA scale assessment of Overall health, hostility were (2020)
M: 4350 to 6 years (Hughes scale) recall and Baseline Depr, associated with lower
Social Isolation - mental status Race, SES (wealth cognitive function, but
rating of index) did not predict it.
frequency of Objective social
meeting, speaking isolation was
or writing with associated with lower
others cognitive function and
Cynical Hostility faster decline of
− 5 item Cook- cognitive function over
Medley Hostility time.
Inventory
Total: 378 Longitudinal study Age: 60–90 Loneliness - De Auditory Verbal Age, Sex, Edu, Alc, Loneliness and social Kuiper et al.
F: 250 (NESDO), (mean 70.7 ± 7.4); Jong Gierveld Learning Test, PA, Depr at network size were not (2020)
M: 128 followed-up to 2 Diagnosis of major or loneliness scale subtest Digit baseline and 2- associated with 2-year
years minor depression or Social Network - Span (both year follow-up cognitive decline in
dysthymia within the first question of forward and depressed patients.
last 6 months the Close Person backward), the Loneliness was
Inventory Stroop Colour- associated with 2-year
word test decline in working
memory.
Total: 14,114 Longitudinal study Age ≥ 50 CESD loneliness Word recall Age, Sex, Edu, Loneliness was Luchetti
F: 54.7 % (SHARE), (mean 63.6) question, 3-item (Immediate, Clinical and associated with et al. (2020)
M: 45.3 % followed-up to 11 no cognitive UCLA loneliness delayed) and behavioral risk increased risk of
years impairment at scale, SI based on animal fluency factors, SI, Depr, cognitive impairment
baseline Mar, children and task PC over time. Lonely
family size participants had twice
the risk of cognitive
impairment compared
to those not feeling
lonely.
Total: 6677 Longitudinal study Age ≥ 50 Social isolation - Physician Soc, Edu, Mar, PC, Loneliness increased Rafnsson
F: 3716 (ELSA), followed- (mean 66) social ties diagnosis of Depr the risk of dementia. et al. (2020)
M: 2961 up to 8 years (contact with dementia or AD, Being married or
children, family) immediate and having close social ties
and involvement delayed recall decreased dementia
in social memory, time risk. Social isolation
organizations orientation was not associated with
Loneliness – dementia.
5
social networks
Revised UCLA
loneliness scale
Total: 1477 Longitudinal, Age ≥ 60 Loneliness Dementia Age, Sex, Edu, Loneliness increased Sundström
F: 777 population-based (mean 71.5) assessed through diagnosis with Depr, PC, Mar, Alc, the risk of all-cause et al. (2020)
M: 700 study (Betula), one question medical records, Smo, dementia and AD, but
followed-up to 20 previous not VaD.
years imaging, Dementia was more
testing/ frequent in females.
interviews,
according to the
DSM-IV
Total: 12,030 Longitudinal study Age ≥ 50 UCLA Loneliness Modified TICS Age, Sex, Edu, Loneliness increased Sutin et al.
F: 60 % (HRS), followed-up (mean 67.30), scale, self-reports Depr, Race, Eth, the risk of dementia by (2020)
to 10 years no dementia at of living status, PC, PA, Smo, 40 %.
baseline presence of APOE-ε4 No sex difference was
children, family, observed.
and friends,
frequency of
contact
Total: 713 Longitudinal study Age ≥ 75 Loneliness MMSE Age, Sex, Edu Loneliness was not a Wang et al.
F: 71 % (CC75C), followed- (mean 86) assessed through risk factor for cognitive (2020)
up to 20 years single question decline over a 20 year
period.
Faster cognitive
decline in women.
Total: 2880 Longitudinal study Age ≥ 45 CES-D; Diagnosis of Age, Sex, Edu, Persistent loneliness Akhter-
M: 1328 (FHS), followed-up (mean 62.1 ± 9) Loneliness dementia and widowhood, SN, was associated with an Khan et al.
F: 1552 to 18 years divided into AD according to ADL, CVD increased risk of AD (2021)
subgroups: the DSM-IV and dementia. Transient
Transient, NINCDS- loneliness was
Incident, ADRDA associated with a lower
Persistent. risk of dementia
compared to not being
lonely.
Total: 18,328 Longitudinal study Age ≥ 65 Revised UCLA Verbal fluency Age, Sex, Edu, Loneliness is a Giné-
(cognitively (SHARE), (mean 75.35), number of chronic predictor of cognitive Garriga
impaired cohort at followed-up to 2 no cognitive illness, Depr impairment. et al. (2021)
wave 5), years impairment at No sex differences for
F: 9674 baseline the incidence of
M: 8654 cognitive impairment.
Total: 617 Longitudinal study Age: 57–97 Loneliness - Several Age, Sex, Edu, Mar, Loneliness was Pugh et al.
F: 77 % (MARS), follow-up (mean 73.31 ± 6.43), modified de Jong- performance- Depr, Social associated with worse (2021)
continuing since African American Gierveld based tests: engagement at global cognition and
2004 adults, MMSE > 23 Loneliness Scale episodic baseline semantic memory at
Social network- memory, baseline but not over
frequency of working time. Increased social
common social memory, activity was associated
interactions semantic with higher global
memory, cognition at baseline
perceptual and over time.
orientation, and
perceptual
speed; multiple
tests for each.
19,092 middle-aged; Cross-sectional Age: 50–64 (middle- Loneliness Word list, digit Age, Sex, Edu, Alc, In middle-aged adults, Smith et al.
13,623 older study (SAGE) aged) and ≥ 65 assessed through span, animal Depr, DM, CVD, lack of association (2021)
adults (older), participants one question naming task; Stroke, SN, SC, between loneliness and
M and F % differs from six countries of self-reported activity, MCI (except China,
based on different low and middle difficulties with South Africa). In older
countries and age income,no dementia daily activities adults, significant
at baseline association between
loneliness and MCI
(China, Mexico, South
Africa, Russia).
Total: 7761 Longitudinal study Age ≥ 50 Loneliness - CES- TICS; episodic Age, Sex, Edu, Alc, Loneliness and social Yu et al.
M: 50.8 % (CHARLS), (mean 60.97) D, Isolation - memory (word Smo, PC, chronic isolation were (2021)
followed-up to 4 Points based on recall) and disease, Depr, area associated with
years marriage, weekly mental status of residence cognitive decline but
contact with association was
children and stronger for social
participation in isolation. Greater
monthly social isolation/loneliness in
activities women.
6
social networks
Total: 155,070 Longitudinal study Age ≥ 60 Social isolation Dementia Age, Sex, Social isolation but not Elovainio
F: 51.9 % (UK Biobank); (mean 64.1) assessed through diagnosis with Socioeconomic loneliness, increased et al. (2022)
followed-up to an three questions. medical records factors including the risk for dementia
average of 8.8 Loneliness Edu, PC, Smo, PA, regardless of genetic
years assessed through Alc, Depr risk levels.
two questions.
Total: 4514 Longitudinal Age ≥ 55 Loneliness MMSE and g- Age, Sex, Edu, Alc, Loneliness was Freak-Poli
M: 2048 studies (Rotterdam (mean 71.3 ± 7.4), assessed through factor tests: Smo, CVD, DM, associated with et al. (2022)
F: 2739 and SNAC-K); MMSE > 25, no one question Verbal Learning BMI, Depr, Mar, cognitive decline and
followed-up to 14 dementia or task, stroop 3 Children increased risk of
and 10 years depression at baseline test, Letter digit dementia. No
substitution association with social
Task, Purdue support.
Pegboard test,
word-fluency
test
Total: 2308 Longitudinal study, Age ≥ 60 CES-D MMSE Age, Sex, Edu Loneliness was Salinas et al.
F: 56 % followed-up to 10 (mean 73 ± 9), associated with an (2022)
years no prevalent dementia increased 10-year
or no dementia incidence of dementia.
follow-up
Total: 462,619 Longitudinal study Mean at baseline: 57, Social isolation Pairs matching Age, Sex, Eth, Social isolation but not Shen et al.
M: 209,975 (UK Biobank); no prevalent cognitive assessed through and reaction socioeconomic loneliness, increased (2022)
F: 252,644 followed-up to an impairment at three questions. time tests factors including the risk for dementia.
average of 11.7 baseline Loneliness Edu, Smo, Alc, PA, Socially isolated
years assessed through PC, APOE individuals had
two questions. genotype, Depr reduced gray matter
volume in various
brain regions.
AD, Alzheimer’s Disease; ADL, Activities of Daily Living; AGECAT, Automated Geriatric Examination for Computer Assisted Taxonomy; Alc, Alcohol use; APOE,
Apolipoprotein E; BC, baseline cognition; CAMCOG, Cambridge Cognitive Examination; CDR, Clinical Dementia Rating Scale; CES-D, Center for Epidemiologic Studies
Depression Scale; CVD, Cardiovascular Disease; Depr, Depression; DM, Diabetes Mellitus; DSM, Diagnostic and Statistical Manual of Mental Disorders; Edu, education;
Emp, Employment; Eth, Ethnicity; FHS, Framingham Heart Study; GMS, Geriatric Mental State; Inc, Income; IQ, Intelligent Quotient; IQCODE, Informant Ques
tionnaire on Cognitive Decline in the Elderly; LNS, Letter Number Sequencing; LSNS-6, Lubben Social Network Scale-6; Mar, Marital status; MCI, Mild Cognitive
Impairment; MMSE, Mini-Mental State Examination; NINCDS-ADRDA, National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer’s Disease
and Related Disorders Association; NINDS-AIREN, International Workshop of the National Institute of Neurological Disorders and Stroke-Association Internationale
pour la Recherche et l’Enseignement en Neurosciences; PA, Physical Activity; PC, Physical Conditions; TICS, Telephone Interview for Cognitive Status; TMT, Trail-
Making Test; RBMT, Rivermead Behavioural Memory Test; SA, Social Activity; SC, Social Class; SI, Social Isolation; Smo, Smoking; SN, Social Network; VaD,
Vascular Dementia; WMS, Wechsler Memory Scale; WSNT, Wenger’s Social Networks Typology.
common symptoms observed in AD patients. different outcomes based on cognitive domains tested at different time
In both cross-sectional and relatively short duration longitudinal points. Despite having a positive effect on measures of global cognition,
studies, an important consideration has been the difficulty to determine higher social activity predicted better performance on episodic memory,
causality. The significant association between loneliness and cognitive perceptual organization and speed but not on working memory (Pugh
decline does not rule out whether cognition itself predicts loneliness et al., 2021). Additionally, a larger social network may not necessarily
over time. A few studies have explored the bidirectionality of this lead to improved cognitive performance but could worsen specific
relationship with mixed results (Donovan et al., 2017; Yin et al., 2019; cognitive domains such as perceptual speed (Pugh et al., 2021). Overall,
Zhong et al., 2017). As increased loneliness leads to a decrease in these findings suggest that interventions aimed at preventing MCI
cognitive performance, cognitive decline may further strengthen future should not solely focus on expanding social networks, but rather on
loneliness, emphasizing a significant bidirectional causal interaction fostering meaningful social connections and engaging in activities that
(Yin et al., 2019; Zhong et al., 2017). However, poorer cognition at promote social interaction.
baseline has not persistently been found to lead to loneliness, especially Despite many studies focusing on the impact of isolation and lone
after adjustment for covariates such as depression (Donovan et al., 2017) liness on cognition, the mechanisms behind this association are not
or within relatively longer follow-ups (Luchetti et al., 2020). Despite the clearly understood. Dysfunction of the hypothalamic–pituitary-adrenal
significant impact of loneliness on cognitive function observed in many (HPA) axis in lonely individuals has been proposed as a potential
studies, a lack of association between loneliness and cognition has also mechanism that may contribute to the impaired cognitive decline
been reported (Evans et al., 2019; Montoliu et al., 2019). Older in (Cacioppo and Hawkley, 2009; Conrad and Bimonte-Nelson, 2010), and
dividuals who lived alone reported greater feelings of loneliness how this irregularity has been linked to a dysfunction in the diurnal cortisol
ever, they were cognitively intact within a two-year follow-up. release (Miller et al., 2007). The negative interaction between loneliness
Interestingly, this cohort of subjects engaged in more frequent social and cognitive performance has been associated with higher cortisol
activity, suggesting that sufficient social relations may counteract the levels at bedtime, strengthening the HPA axis dysfunction hypothesis
effects of loneliness (Evans et al., 2019). Engaging in activities that (Montoliu et al., 2019). The more pronounced association of social
involve social interaction (i.e. social activity) and having a diverse social isolation and loneliness with poor cognitive health in individuals with
network which could reduce social isolation, was associated with better lower education levels (Steptoe et al., 2013) suggest that building
global cognition and episodic memory in adults, supporting the impor cognitive reserve may be effective in establishing resilience against
tance of social interaction in preserving cognition (Kuiper et al., 2020; loneliness-induced cognitive impairment. Cognitive impairment exac
Pugh et al., 2021). Yet, the impact of social engagement could have erbated by isolation and loneliness may also be due to an accelerated
7
neurodegenerative ageing process. Being a risk factor for chronic et al., 2011). However, as covariates including physical activity, phys
inflammation and stress, social isolation may have a significant role in ical condition, and depression are often adjusted for in the statistical
disrupting the brain areas involved in cognitive function. Other analysis, this argument has low validity with regards to the existing
contributing factors may include lack of physical activity, worsened literature (Table 1).
sleep quality, chronic drinking, or smoking (see review (Cacioppo and Two potential explanations for the relationship between being iso
Hawkley, 2009)). Further research must be conducted on testing these lated or lonely and dementia are the stress hypothesis and the cognitive
postulates. reserve hypothesis (Penninkilampi et al., 2018). The stress hypothesis
suggests that loneliness acts as a stressor in the body, stimulating the
2.2. Social isolation and loneliness as risk factors for dementia and AD sympathetic nervous system and causing an upregulation of glucocor
ticoid secretion and inflammation (Sapolsky, 1999; Sundström et al.,
Numerous studies have used a longitudinal design to investigate 2020), damaging the susceptible brain areas including the orbital pre
social isolation and/or perceived loneliness as a risk factor for dementia frontal cortex, medial prefrontal cortex and the hippocampus (Cacioppo
and AD (Table 1). In these studies, loneliness at baseline was associated et al., 2014; Sutin et al., 2020). According to the cognitive reserve hy
with rapid cognitive decline and an increased risk of dementia (Akhter- pothesis, individuals exhibit variable degrees of resilience to cognitive
Khan et al., 2021; Freak-Poli et al., 2022; Poey et al., 2017; Rafnsson decline. The degree of reserve can be influenced by various factors and
et al., 2020; Salinas et al., 2022; Sundström et al., 2020; Sutin et al., may be reduced by loneliness (Wilson et al., 2007). While lonely in
2020; Wilson et al., 2007; Zhou et al., 2018), while others reported a dividuals may not receive as much neural stimulation from their social
significant association between social isolation and dementia risk (Elo environment, engagement in social activities can serve as a protective
vainio et al., 2022; Fratiglioni et al., 2000; Grande et al., 2018; Poey factor for neural systems related to social behavior through additional
et al., 2017; Shen et al., 2022; Yu et al., 2021). A number of variable but mechanisms including changes in neurogenesis (for review (Holmes,
informative conclusions have emerged across different studies. A 3-year 2016; Lieberwirth and Wang, 2012)).
follow-up on Chinese adults aged 65 and older reported a significant
interaction between loneliness and gender on dementia risk. Accord 2.3. Social isolation and loneliness on AD pathology and imaging studies
ingly, loneliness had a more profound effect in men, increasing the de
mentia risk significantly when compared with women (Zhou et al., Despite the strong association between loneliness and AD, the effect
2018). The finding that loneliness is a significant risk factor for all-type of loneliness on AD-related pathology is largely unknown. The post-
dementia and AD but not for vascular dementia revealed an important mortem analysis of human brain tissue has not always revealed an as
association of loneliness with particular dementia subtypes (Sundström sociation of loneliness with an exacerbated AD-related pathology,
et al., 2020). Recent research has found a strong correlation between despite the increased risk of dementia in these patients (Wilson et al.,
dementia risk and social isolation, but not with loneliness (Elovainio 2007). While the finding that loneliness is not associated with AD-
et al., 2022; Shen et al., 2022). After controlling for social isolation and related pathology can refute the reverse causality mechanism of cogni
depressive symptoms, the relationship between loneliness and dementia tive decline, this has been challenged by recent studies that determined
was found to be non-significant. This suggests that the presence of two amyloid and tau burden using positron emission tomography (PET) in
risk factors for dementia, loneliness and depression, may lead to cognitively normal participants (d’Oleire Uquillas et al., 2018; Donovan
different outcomes depending on the health status of the subjects. The et al., 2016). In a cross-sectional analysis of 79 cognitively normal in
association of persistent but not transient loneliness with dementia risk dividuals, participants with high cortical amyloid burden (defined as
indicate that the degree of loneliness may also be an important factor to individuals with a Pittsburgh Compound B-PET distribution volume
consider when assessing dementia risk (Akhter-Khan et al., 2021). ratio > 1.2) were 7.5 more likely to report high levels of loneliness as
While many of the aforementioned studies showed social isolation compared to amyloid-negative individuals. This association was stron
and/or perceived loneliness has an association with dementia, several ger in higher-risk individuals carrying the APOEε4 allele (Donovan
studies hold conflicting results. A large randomized longitudinal study et al., 2016). In cognitively healthy older adults, the cortical amyloid
with a follow-up period of 16 years found no significant association burden was negatively correlated with the level of social engagement
between social relationships and risk of all-cause dementia or AD after (Biddle et al., 2019). Those who reported being lonely showed greater
exclusion of participants with a survival time of three years (Sörman tau pathology in the entorhinal cortex, which is a region affected early in
et al., 2015). However, the authors quantified the relationship index AD (d’Oleire Uquillas et al., 2018). This suggested a potential circuit-
based on living status and the number of social contacts, rather than related mechanism not only affecting the entorhinal cortex but the
qualitative aspects including satisfaction with relationships or feeling overall connectivity with the brain regions involved in socioemotional
lonely. Although a lack of social ties has been shown to be a risk factor in processing, which could ultimately lead to a greater loneliness. In sup
previous studies (Grande et al., 2018; Poey et al., 2017), more extensive port with this, individuals with a larger social network performed better
social support among older individuals may also indicate that partici at cognitive tasks despite the presence of AD pathology, suggesting that
pants are in poorer health due to a greater presence of other risk factors social network size is a strong modifying factor in the association be
and comorbidities. Therefore, it is important to consider an extensive tween cognitive decline and pathological changes (Bennett et al., 2006).
and detailed analysis of social factors among older individuals to The relation between loneliness and brain structure in individuals
improve the identification of causal relationships. living with or at high risk for clinical AD has recently been investigated.
Various mechanisms have been proposed in the study of loneliness as Whole brain voxel-based morphometry analysis revealed decreased gray
a risk factor for dementia and AD. As previously mentioned, loneliness matter volume in bilateral thalamus, left middle occipital gyrus and
could be considered a consequence of dementia (Cacioppo and Hawkley, cerebellar vermis lobules in lonely patients, when compared with those
2009), which may suggest that cognitive decline limits social relation who did not feel lonely (Zhang et al., 2022b). This was reflected in the
ships (Lang, 2001), despite a lack of a relation between loneliness and greater cognitive changes observed in lonely patients in the early stages
the pathological markers of AD in post-mortem analysis (Wilson et al., of the disease. Of note, this association was only evident in patients at
2007). The robust associations between loneliness and dementia found high risk for AD, suggesting the possibility of greater vulnerability to the
after sensitivity analysis in various studies also refute the reverse cau progression of AD-related pathology and cognitive decline. The reported
sality mechanism (Rafnsson et al., 2020; Sundström et al., 2020; Sutin absence of changes in the gray matter volume or cognition between
et al., 2020). Alternatively, it has been proposed that lonely individuals lonely and non-lonely AD patients may stem from the methodological
may engage in behaviors that lead to other risk factors of dementia, such difficulties at a progressed disease stage and necessitates more studies
as decreased physical activity (Hawkley and Cacioppo, 2010; Shankar focused on the pathological changes at early stages of AD. Magnetic
8
resonance imaging (MRI) in dementia-free subjects revealed reduced et al., 2006; Paillard-Borg et al., 2009; Verghese et al., 2003; Wang et al.,
total cerebral volume and increased white matter hyperintensity vol 2002; for review, Su et al., 2022). However, passive behaviors and social
ume, indicating a decrease in brain volume accompanied by greater withdrawal which are among the prominent behavioral symptoms of AD
white matter injury compared to non-lonely subjects (Salinas et al., and dementia, may likely contribute to the further cognitive decline if
2022). Whole-brain analysis in isolated individuals revealed significant physical and social support interventions are not early enough in the
reductions in the volumes of brain regions critical for cognition disease course (Heser et al., 2014; Kolanowski and Buettner, 2008).
including but not limited to the medial temporal lobe, hippocampus, The majority of the studies discussed above benefited from having a
ventromedial prefrontal cortex, and thalamus (Shen et al., 2022). These large sample size, prolonged follow-up period, controlling for many
studies suggested that individuals suffering from isolation or loneliness demographic confounding variables and investigating social in
demonstrate neuroanatomical changes related to AD vulnerability teractions using multiple measures. However, these studies also high
placing them at an increased risk for AD and related dementia. lighted potential shortcomings. Despite having large overall sample
sizes, some studies included a small number of participants in each so
2.4. Social network as a protective factor for dementia and AD cial category they investigated (e.g. high versus low social engagement)
(Amieva et al., 2010; Rodriguez et al., 2018; Sundström et al., 2020). A
Can social interactions act as a protective factor for dementia and common concern when recruiting for these studies was selection and
AD? To study social relationships, several variables, including social recall bias and reverse causation. While the studies excluded individuals
network, frequency of contact, the participant’s degree of satisfaction with dementia at baseline, the presence of early cognitive impairment
with the relationship, participation in social activities and social may not have been completely ruled out (Crooks et al., 2008; Heser
engagement, have been investigated (Pillai and Verghese, 2009). Social et al., 2014; Sörman et al., 2015; Sundström et al., 2014). Early cognitive
network size and composition have been identified to influence the decline may result in the decreased levels of social contact and social
incidence rate of dementia and AD (Crooks et al., 2008; Fratiglioni et al., withdrawal or a failure to recall social support. The potential con
2000). Individuals with a small social network have a 60 % increased founding effects of these factors may weaken the association between
risk of dementia (Fratiglioni et al., 2000) while more extensive social certain measures of social support and reduced dementia risk (Crooks
networks and more frequent social interactions were found to have a et al., 2008; Heser et al., 2014). Not all social interaction measures have
decreased risk of dementia (Amieva et al., 2010; Balouch et al., 2019; formal questionnaires, and the lack of a standard scale may limit
Crooks et al., 2008; Sörman et al., 2015; Zhou et al., 2018). Additionally, reproducibility. Likewise, using self-reported measures of social contact
the diversity of the social network could impact the rate of incident may be influenced by reporting bias (Crooks et al., 2008; Khondoker
dementia with individuals with a “restricted” social network being twice et al., 2017; Sommerlad et al., 2019). The potential underestimation of
more likely to develop dementia (Rodriguez et al., 2018). the association between social support and incident dementia due to
Multiple studies suggest that having high-quality social relationships these limitations requires further research to fully understand the
can reduce the risk of dementia (Amieva et al., 2010; Khondoker et al., relationship.
2017). In community-dwelling seniors over the age of 65, satisfaction
and perception of reciprocity within a social network reduced the risk of 2.5. Summary
dementia and AD (Amieva et al., 2010). Individuals who felt well un
derstood by their social network experienced a slower cognitive decline Of the studies included in Table 1, the majority (19 out of 34; 55.8 %)
rate and were at a lower risk of dementia (Marioni et al., 2015). The type investigated the association between loneliness and the future risk for
of support provided to patients from their social network is also signif cognitive impairment or dementia. Four studies (11.8 %) investigated
icantly associated with reduced risk of dementia. Participants receiving the effects of isolation or networks while eleven studies (29.4 %) eval
positive support from their children had a decreased incident risk of uated the association for both loneliness and social isolation. Among the
dementia, while negative interactions with family members increased studies that focused on loneliness alone, nine reported a positive asso
this risk (Khondoker et al., 2017). A larger social network composed of ciation with loneliness and future cognitive impairment (Donovan et al.,
friends but not family was suggested to protect against rapid cognitive 2017; Freak-Poli et al., 2022; Giné-Garriga et al., 2021; Lobo et al., 2008;
deterioration in AD patients, possibly due to increased intellectual social Luchetti et al., 2020; Montoliu et al., 2019; O’Luanaigh et al., 2012;
relationships (Balouch et al., 2019). Practical support increased the risk Smith et al., 2021; Yin et al., 2019) while four reported mild (Kuiper
for dementia and AD although it could reflect an early symptom of the et al., 2020) or no association (Balouch et al., 2019; Pugh et al., 2021;
disease, indicating that participants required assistance with specific Wang et al., 2020). Seven studies reported a significant correlation be
tasks (Heser et al., 2014). Additionally, being widowed and not having tween loneliness and dementia (Freak-Poli et al., 2022; Holwerda et al.,
children increased the risk for dementia (Sundström et al., 2020). 2014; Salinas et al., 2022; Sundström et al., 2020; Sutin et al., 2020;
The frequency of contact within a social network is an additional Wilson et al., 2007; Zhou et al., 2018) and two studies found a signifi
factor inversely associated with dementia and AD (Sommerlad et al., cant association between social isolation and increased likelihood of
2019; Sörman et al., 2015; Zhou et al., 2018). A high social relationship developing dementia (Fratiglioni et al., 2000; Grande et al., 2018). The
index and greater social engagement decrease the risk of dementia or AD studies that evaluated the correlation with both loneliness and social
(Sörman et al., 2015; Zhou et al., 2018). Social engagement levels of isolation yielded mixed results. Three studies reported a positive asso
dementia patients were low prior to their diagnosis and decreased ciation for both loneliness and isolation with progressive cognitive
further as the disease progressed (Hackett et al., 2019). Interestingly, a decline (Poey et al., 2017; Shankar et al., 2013; Zhong et al., 2017) or
significant association observed between dementia and social contact dementia (Poey et al., 2017). Three studies found a significant associa
with friends, was not observed for social contact with relatives (Som tion for progressive cognitive decline with social isolation only (Evans
merlad et al., 2019) suggesting that not only the frequency but also the et al., 2019; Griffin et al., 2020; Yu et al., 2021). Two studies reported a
type of contact is critical in the protection against dementia. significant association between social isolation and dementia risk, but
In addition to social variables, studies investigated the relationship no association was found with loneliness after adjusting for depressive
between overall leisure activities and dementia. Leisure activities are symptoms (Elovainio et al., 2022; Shen et al., 2022). These results
typically categorized into physical, cognitive and social activities. suggest that the pre-existing cognitive impairments (Evans et al., 2019;
Physical activity has been associated with reduced mortality across Griffin et al., 2020; Pugh et al., 2021) or depressive symptoms in lonely
multiple studies (Arem et al., 2015; Kujala et al., 1998; Leitzmann et al., subjects (Kuiper et al., 2020; Yu et al., 2021) may likely confound the
2007). Participation in cognitive and physical activities has been asso correlation between loneliness and progression of cognitive decline.
ciated with a decrease in dementia and AD risk (Heser et al., 2014; Karp The positive impact of social network on reducing the likelihood of
9
cognitive decline and dementia is largely attributed to the quality and 2020; Medendorp et al., 2018; G. Park et al., 2021; Sargin et al., 2019;
diversity of social connections. For instance, the effect of infrequent Yamamuro et al., 2020; Zelikowsky et al., 2018; reviewed in (Lee et al.,
social contact did not necessarily predict dementia if the contacts were 2021; Lukkes et al., 2009b; Matsumoto et al., 2019). Animal models
deemed satisfying (Fratiglioni et al., 2000). Receiving positive support, have provided invaluable insight into the mechanisms underlying social
being well understood, and perception of reciprocity all contribute to a isolation-induced deficits in learning and memory (Hsiao et al., 2011;
slower cognitive decline (Marioni et al., 2015) and reduce incident risk Huang et al., 2011; Lavenda-Grosberg et al., 2022), with potential
of dementia (Amieva et al., 2010; Khondoker et al., 2017; Marioni et al., treatment approaches (Cao et al., 2018; Dong et al., 2004; Ren et al.,
2015). A large and extensive social network composed of not only family 2015; Uys et al., 2016), which have been summarized previously (Ara
but also friends provides greater protection against cognitive decline kawa, 2018; Fone and Porkess, 2008; Lee et al., 2021). Growing evi
and dementia (Balouch et al., 2019; Crooks et al., 2008; Rodriguez et al., dence indicates the potential bidirectional links between social deficits
2018; Sommerlad et al., 2019; Sörman et al., 2015). In consistent with or isolation and behavioral dysfunction in AD (Drinkwater et al., 2022;
these studies, being widowed, having no children or experiencing Shen et al., 2022), suggesting an urgent need to better understand the
negative social interactions increase the risk for dementia (Khondoker mechanisms in order to develop intervention strategies.
et al., 2017; Sundström et al., 2020). Altogether, these findings suggest Here, we will review the evidence of social isolation-induced deficits
that a large social network may still have a negative impact if not sup in cognition in animal models of AD. We will also summarize changes in
portive (Khondoker et al., 2017; Pugh et al., 2021), and the quality and AD-specific pathologies, inflammatory responses, and stress hormone
diversity of a large network, rather than its size, predict protection levels reported in these studies. We will conclude by discussing the
against cognitive decline or dementia. mechanisms underlying the protective effects of physical and social
Recent studies using imaging technologies have identified AD- enrichment in AD animal models.
related pathological hallmarks in the cortical regions of patients
suffering from loneliness (Biddle et al., 2019; d’Oleire Uquillas et al., 3.2. Impact of social isolation on cognition in animal models of AD
2018; Donovan et al., 2016). Moreover, reduced brain volume (Salinas
et al., 2022; Zhang et al., 2022b) and increased white matter injury A vast amount of research reported the long-term effects of social
(Salinas et al., 2022) in lonely subjects as identified by these studies isolation on cognitive function and/or affective behavior across
provided a great insight into the loneliness-induced pathological different model organisms including mice (Dong et al., 2008, 2004;
changes in the brain. With the ability to detect pathological changes in Hsiao et al., 2012, 2011; Huang et al., 2015, 2011), rats (Ali et al., 2017;
the brain before the onset of dementia, these studies offer the potential Gong et al., 2017; Ren et al., 2015), O. degus (Pereda-Pérez et al., 2013;
for predicting the progression of cognitive decline. The early identifi Rivera et al., 2020), drosophila melanogaster (Ruland et al., 2018) and
cation of pathological markers associated with AD vulnerability through rhesus macaques (Sallet et al., 2011). The impact of social isolation on
imaging studies presents an opportunity for interventions, such as the progression of AD has been studied in rodent transgenic AD models
increasing social engagement, to prevent cognitive deterioration. (Table 2), including the Tg2576 (Dong et al., 2008, 2004; Kang et al.,
The mechanisms underlying the association between these patho 2007), SAMP8 (Zhang et al., 2022a), amyloid precursor protein (APP)/
logical changes, social variables, dementia and AD remain to be eluci presenilin-1 (PS1) (Cao et al., 2018; Hsiao et al., 2012, 2011; Huang
dated. Increased social contact has been hypothesized to decrease stress et al., 2015, 2011), 3xTg (Joshi et al., 2014; Pietropaolo et al., 2009),
levels through endocrine response (Uvnäs Moberg and Petersson, 2006). and 5xFAD mice (Peterman et al., 2020) (also see rodents infused with
Another plausible explanation is social buffering that contributes to amyloid beta (Aβ)1-42 (Tamano et al., 2016) and aluminium chloride
patients with high social support to experience reduced stress levels (AlCl3) (Ali et al., 2017)). Social isolation during adolescent develop
(Gellert et al., 2018; Gunnar and Hostinar, 2015). Social interactions ment can be modeled by single-housing animals right after weaning
may also decrease the risk of AD by decreasing the inflammatory (postnatal day 21 for rodents; early-life/post-weaning social isolation)
response (Kiecolt-Glaser et al., 2010). Having a larger social network (Cao et al., 2018; Dong et al., 2008, 2004; Hsiao et al., 2012, 2011; Kang
and being socially well-integrated decreased the level of proin et al., 2007; Pietropaolo et al., 2009). Isolation during adulthood in
flammatory cytokine, interleukin-6, and C-reactive protein in older men volves single-housing animals after they have reached sexual maturity
(Ford et al., 2006; Loucks et al., 2006a, 2006b). Individuals with greater (6–8 weeks for rodents) (Huang et al., 2015, 2011; Joshi et al., 2014;
social and emotional support had higher levels of brain-derived neuro Liang et al., 2019; Peterman et al., 2020; Tamano et al., 2016; Zhang
trophic factor (BDNF) that can counteract inflammation and increase et al., 2022a). These studies (as listed in Table 2) help determine the
neuroprotection (Salinas et al., 2017). These findings emphasize the effects of isolation during adolescent development or later in life.
necessity of social engagement as an intervention method prior to or Remarkably, AD-specific pathological changes and cognitive deficits
during the preclinical stages of AD. Further insight into the mechanisms have been robustly observed after chronic social isolation (Dong et al.,
with the help of additional studies in animal models is required to 2008, 2004; Huang et al., 2015).
develop novel prevention and treatment approaches.
3.2.1. AD-related cognitive impairment and pathology
3. Loneliness and AD in animal models In rodent models, cognitive performance has been assessed by a
variety of tests including the Morris water maze (MWM) (spatial
3.1. Animal models of social isolation learning/memory), Y-maze (short term memory/spatial recognition
memory), Novel Object Recognition Test (NORT) (object recognition
The effect of social isolation on brain function and behavior has memory), and fear conditioning test (contextual or cued fear memory).
extensively been studied in animals, particularly in rodents (Fone and The majority of studies in animal models of AD reported deficits in
Porkess, 2008). Depriving rodents of social contact by single housing spatial learning and memory (Cao et al., 2018; Gong et al., 2017; Huang
them in the laboratory environment has long been used as a model of et al., 2015, 2011; Liang et al., 2019; Pietropaolo et al., 2009), short-
psychosocial stress. Extensive research showed that isolation in rodents term memory (Huang et al., 2015), spatial recognition memory (Cao
leads to long-lasting deficits including impaired social and cognitive et al., 2018; Pietropaolo et al., 2009), object recognition (Gong et al.,
function (Hinton et al., 2019; Liu et al., 2018; Medendorp et al., 2018; 2017; Tamano et al., 2016; Uys et al., 2016), and fear memory
Niwa et al., 2011), increased anxiety- and depressive-like behaviors (Du (contextual (Dong et al., 2004; Hsiao et al., 2012, 2011; Joshi et al.,
Preez et al., 2020; Lee et al., 2020; Lukkes et al., 2009a; Sargin et al., 2014; Peterman et al., 2020) and cued (Joshi et al., 2014)), which are
2016) accompanied by pathological alterations in various brain regions typically identified early in the progression of the disease. A substantial
and circuits that are critical for socioemotional regulation (Bicks et al., number of studies focused on the impact of social isolation in AD models
10
Table 2
Social isolation in animal models of Alzheimer’s Disease.
Model Sex Isolation Age and Period Behavioral Analysis SI induced Pathology Original
Publication
Tg2576 Female + PND 21 – 6 months of age Contextual and cued fear Histology: Dong et al.
Male conditioning: BrdU+ cells in the hippocampus (dentate gyrus) at (2004)
(sex difference Contextual fear months 3, 6 and 9:↓ (Note the decrease in controls as
is not memory:↓ well over time)
analyzed) Cued memory:= Hippocampal cell proliferation when assessed at
month 6:↓
Aβ plaques in cortex and hippocampus:↑
Therapeutic strategy:
Fluoxetine treatment restored SI-induced decrease in
cell proliferation. No effect of fluoxetine on plaque
formation
Female + PND 21 – 4 months of age; also NA ELISA: Kang et al.
Male comparison with acute restraint Interstitial Aβ levels:↑ (2007)
(sex difference stress ApoE:=
is not CRF:=
analyzed) Immunoblotting:
Full-length APP, the α- and β- C-terminal fragment
(CTF) of APP:=
Insulin degrading enzyme and neprilysin:=
(Increased CRF after acute restraint but not in mice

subjected to SI → acute vs chronic stress may affect Aβ
levels via different mechanisms)
Female + PND 21– 27 weeks of age NA Radioimmunoassay: Dong et al.
Male Corticosterone:↑ (2008)
(sex difference
is not ELISA:
analyzed) Aβ1-40 and Aβ1-42:↑
Histology:
Glucocorticoid receptor (GR) and CRF receptor
(CRFR1):↑
GR+ and CRFR1+ cells in cortex and hippocampus:↑
Hippocampus volume:↓
APP/ Male 12– 28 weeks of age MWM: ELISA: Huang et al.
PS1 mice Spatial reference Aβ42/Aβ40 ratio in hippocampus:↑ (2011)
memory: =
Spatial working memory: Histology:
↓ Manganese superoxide dismutase (MnSOD) levels in
the CA1–CA3 subregions of the hippocampus,
basolateral part of the amygdala (BLA), and locus
coeruleus (LC):↑
Cholinergic cells in the diagonal band of Broca (DB),
noradrenergic neurons in LC, serotonergic neurons in
the Raphe nucleus:↓
Immunoblotting:
Levels of NMDA 2B receptor (NR2B) in
hippocampus:↓
Male PND 28 – 3 months of age Fear Conditioning: Electrophysiology: Hsiao et al.
Contextual fear LTP in the hippocampal CA1 neurons:↓ (2011)
memory:↓
Cued fear memory: = ELISA:
Aβ40 and 42 levels:↑
β and γ-secretase enzyme activity (enzymes that
cleave APP to produce Aβ):↑
Immunoblotting and Immunoprecipitation:

p25/p35 ratio:↑
Cdk5 activity:↑
Calpain activity assay kit:

Calpain activity:↑
Calpain inhibitor (calpeptin) and proteasome
inhibitor (MG132): prevented the SI-induced-
decrease in p35 and SI-induced decrease in fear
memory and LTP.
Male PND 28 – 11 weeks of age CFC: Immunoblotting: Hsiao et al.
Contextual fear memory: LTP:↓ (2012)
↓ Hippocampal Aβ40 and Aβ42:↑
11
Publication
Antioxidant activity:↑
p35/Cdk5 activity:↓
GluR1 Ser831 phosphorylation, surface expression of
AMPARs, and p35-GluR1-CaMKII interactions:↓
N-acetylcysteine (NAC): prevented SI-induced
impairment of contextual fear memory and decreased
of hippocampal LTP.
Male 17 months – 20 months of age MWM: Histology and Immunoblotting: Huang et al.
Spatial learning memory, Aβ and γ-secretase levels:↑ (2015)
long-term memory: ↓ Insulin degrading enzyme and neprilysin, proteolytic
enzymes (eliminate Aβ):↓
Y-maze: Hippocampal volume (particularly white matter):↓
Short-term memory: ↓ Synapse and myelin-related proteins:↓
Reactive astrocyte and microglia levels surrounding
OFT: amyloid plaques in hippocampus:↑
Anxiety-like behavior:
mild
Male PND 28 for 8 weeks MWM: Histology and Immunoblotting: Cao et al.
Spatial reference Apoptosis signaling, caspase-3, in SI condition at (2018)
memory: ↓ month 3:↑
Key factors in NF-κB inflammasome activation:↑
Y-maze: Proapoptotic (BAX):↑
Spatial recognition Antiapoptotic factor (Bcl-2):↓
memory: ↓ GFAP + astrocytes: ↑
APP production:=
EE reversed spatial cognitive decline, and rescued
cellular apoptosis (Caspase-3), synaptic loss (SYN,
PSD-95), neuroinflammation, NLRP3 inflammasome
signaling pathways and glial activation in the hippo
campus, did not affect APP processing.
Male 6 months of age for 6 months Compared with SI, SCF: Compared with SI, SCF: Liang et al.
Grouped: a social isolation (SI) MWM: Immunoblotting: (2019)
groups, a social contact with one Spatial reference Amyloidogenic related protein:=
mouse (SCO) group, and a social memory after 6 months: ↑
contact with five mice (SCF) group Reagent kits:
α/β-secretase activity:=
ELISA:
Aβ40 and Aβ42:=
Histology:
Amyloid plaque deposition:=
Astroglial activation:↑
Dendritic sprouting and branching:↑
Synaptic loss:↓
Electrophysiology:
Dendritic interactions in hippocampus:↑
Miniature excitatory synaptic current (mEPSC): ↑
Flow cytometry:
Astrocytic and astrogliosis in hippocampus:↑
RT-PCR:
Microglia: pro-inflammatory stage → anti-
inflammatory
3xTg mice Female + PND 21 – 6 month of age EPM: Histology: Pietropaolo
Male Anxiety-like behavior: Hippocampal Aβ pathology:= (females > males) et al. (2009)
↑(tg females) AD-like behavioral symptoms and pathology:=
Locomotor activity: ↑ (Independent of sex)
OFT:
Locomotor activity: ↑
Acoustic startle reflex: ↑
MWM:
Spatial learning and
memory: ↓
Y maze:
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Spatial recognition
memory: ↓
Locomotor activity: ↑
Female Restraint/isolation (R/I) stress Y-maze: ELISA: Joshi et al.
administered for 60 min a day, 6 Short-term memory: = Plasma corticosterone, leukotriene B4:↑ (2014)
days/week, for 4 weeks at age 4 – 4.5 Fear conditioning: Aβ levels:=
months Contextual and cued
recall long-term memory: Immunoblotting:
↓ Levels of the glucocorticoid receptor:=
Tau phosphorylation and solubility:↑
GSK3β kinase activity:↑
Electrophysiology:
LTP:↓
Absence of Arachidonate 5-lipoxygenase (ALOX5)
gene prevented stress-induced memory deficits, syn
aptic dysfunction and tauopathy
5xFAD Male 2 months of age for 2 or 3 months CFC: ELISA: Peterman
mice Hippocampus dependent Hippocampal Aβ levels:= et al. (2020)
learning and memory: ↓
Histology:
Hippocampal plaques:↑
Immunoblotting:
Beta-secretase 1 (BACE 1):↑
Exercise and EE did not prevent SI-induced cognitive
deficits
ddY mice Male 4- and 11-weeks old for 2–3 weeks OFT: = Corticosterone[125I] radioimmunoassay kit Tamano et al.
injected with Resident-intruder test Corticosterone:↑ (2016)
Aβ1-42 Aggressive behavior:↑ Potassium chloride-induced exocytosis (presynaptic
activity):↑
EPM:
Anxiety-related
behavior:↑
Object recognition
memory:↓
Sprague- Male ? for 4 weeks NA Test kit: Ali et al.
Dawley rats Brain Acetylcholine Esterase (ACHE):↑ (2017)
(injected
with AlCl3) Oxidative stress markers:
MDA:↑
SOD:↓
TAC:↓
Agarose gel electrophoresis:

Apoptosis and DNA fragmentation:↑
ELISA:
Aβ:↑
BDNF:↓
IL-1β:↑
TNF-α:↑
Fluorometric assay:
DA, NE, 5-HT:↓
Histology:
Focal nuclear pyknosis and degeneration in cortical
cells associated with atrophy in substantia nigra.
Nuclear pyknosis and degeneration with congestion
in the blood vessels in hippocampus, fascia dentate
striatum and substantia nigra.
SAMP8 mice Male At 3 months for 4 weeks Odor-based reversal Histology: Zhang et al.
learning and delay-based Basolateral amygdala (BLA) neurons:↓ (2022a)
flexible decision-making
Behavioral flexibility: ↓ Immunoblotting:
OFT: = RIPK3, pRIPK3, MLKL and pMLKL in BLA: ↑
EPM: Membrane translocation of pMLKL:↑
Anxiety-like behavior: GSK-3α:↓
slightly ↑ GSK-3β:=
mTORC1 signaling:↑
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AAV-GSK-3α injection into the BLA or inhibition of
mTORC1 signal by rapamycin administration:
behavioral flexibility alleviated
AAV, Adeno-Associated Virus; Aβ, Amyloid-beta; APP, Amyloid Precursor Protein; BDNF, Brain Derived Neurotrophic Factor; BLA: Basolateral Amygdala; Cdk5, Cyclin
dependent kinase 5; CFC, Contextual Fear Conditioning; CRF, Corticotropin-Releasing Factor; DA, Dopamine; EE, Enriched Environment; ELISA: Enzyme-Linked
Immunosorbent Assay; EPM, Elevated Plus Maze; GSK, Glycogen Synthase Kinase; 5-HT, 5-Hydroxytryptamine; IL-1β, Interleukin 1-beta; LTP, Long Term Potentia
tion; MDA, Malondialdehyde; MLKL, Mixed Lineage Kinase domain-like protein; MWM, Morris Water Maze; NA, Not Available; NAC, N-Acetylcysteine; NE,
Norepinephrine; NORT, Novel Object Eecognition Test; OFT, Open Field Test; ORM, Object Recognition Memory; PND, Postnatal Day; RIPK3, Receptor Interacting
Protein Kinase-3; RIT, Resident-Intruder Test; SI, Social Isolation; SOD, Superoxide Dismutase; TAC, Total Antioxidant Capacity; Tg, Transgenic; TNF-α, Tumor Ne
crosis Factor-alpha; ↓, decreased;↑, increased; =, no change.
identified that cognitive impairments were exacerbated by social isola model that recapitulates age-related cognitive decline, GSK-α is reduced
tion stress (Y-maze: short-term (Joshi et al., 2014) and cued fear con in the BLA (Zhang et al., 2022a) while GSK-3β is excessively active in the
ditioning (Dong et al., 2004; Hsiao et al., 2011)). In animal models of hippocampus of socially isolated male Sprague Dawley (SD) rats (Gong
AD, social isolation-induced disruption in cognitive performance has et al., 2017; Ren et al., 2015). These changes in GSK3 can only
been associated with accelerated Aβ plaque deposition (Hsiao et al., contribute to the abnormal phosphorylation of tau (Ren et al., 2015), but
2012, 2011; Huang et al., 2011), abnormal phosphorylation of the can also lead to the increased production of Aβ, apoptosis, necroptosis
microtubule-binding protein tau (Joshi et al., 2014), enhanced neuro and memory dysfunction (Gong et al., 2017; Hooper et al., 2008; Ren
inflammation (Ali et al., 2017; Cao et al., 2018; Liang et al., 2019) and et al., 2015).
abnormal corticosterone levels (Dong et al., 2008; Tamano et al., 2016),
with reduced hippocampal adult neurogenesis (Dong et al., 2004), and 3.2.2. Neuroinflammation
loss of synapses (Cao et al., 2018; Liang et al., 2019). These findings Neuroinflammatory mechanisms play a fundamental role in the
suggest that social isolation stress induces and exacerbates the pathol progression of AD-related pathological changes and dementia (Heppner
ogy underlying cognitive impairment, reinforcing its role as a significant et al., 2015). Neuroinflammatory changes have been identified among
risk factor for the outcome of memory impairment. the mechanisms underlying the social isolation-induced disease pro
The most common methodology to assess AD-related pathology in gression. Socially isolated male APP/PS1 mice (8 weeks at post-natal
animal models is the extent of Aβ plaque deposition and the presence of day (PND) 28) show increased levels of proinflammatory cytokines
neurofibrillary tangles, which are also the critical neuropathological and inflammasomes in the hippocampus, indicating increased neuro
hallmarks in clinical AD. Chronic social isolation in AD animal models inflammation, that can contribute to apoptosis and decreased synaptic
was reported to increase the degree of Aβ plaque deposition and tau activity observed in this region (Cao et al., 2018). As astrocytes and
phosphorylation in the hippocampus, which is critical for spatial microglia are critical modulators in inflammatory response, and play a
memory (Dong et al., 2008, 2004; Hsiao et al., 2014, 2012,2011; Huang role in the progression of AD (Fernandez et al., 2019; J.-S. Park et al.,
et al., 2015, 2011). Long-term social isolation (e.g. > 2 months) elevates 2021), the changes in these cell types have also been studied in social
the expression of hippocampal β-Site APP-cleaving enzyme (BACE1) isolation models (Liang et al., 2019). Socially isolated male APP/PS1
(Peterman et al., 2020), β- and γ-secretase activity (Hsiao et al., 2011; mice (6 months at 6 months of age) show increased mRNA levels of
Huang et al., 2015), leading to an increase in the production of Aβ neuroinflammatory genes (Ccl2, Ccl4, Casp1, Tlr4) in hippocampal as
peptides, in both male 5xFAD (Peterman et al., 2020) and APP/PS1 mice trocytes, compared with group-housed APP/PS1 mice (Liang et al.,
(Hsiao et al., 2011; Huang et al., 2015). Increased Aβ levels have been 2019). The pro-inflammatory gene (Il1β, Il6rα, Casp1, Nlrp3) and protein
associated with a greater impairment in hippocampus-dependent (IL-1α, IL-1β, TGFβ, TNF α) levels are increased while the anti-
memory and long-term potentiation (LTP) in socially isolated male inflammatory gene (Il4, Il4rα) and protein (IL-4, IL-10) levels are
APP/PS1 transgenic mice, compared with the group housed APP/PS1 decreased in microglia obtained from the hippocampus of isolated APP/
transgenic mice and wild-type isolated mice (Hsiao et al., 2011; Huang PS1 mice, when compared with group-housed animals (Liang et al.,
et al., 2011). Aβ accumulation accelerates the conversion of p35, a 2019). These observations suggest that social isolation, during adoles
cyclin-dependent kinase 5 (Cdk5) activator, to p25, resulting in the cence or adulthood in APP/PS1 mice increase the transition of anti-
accumulation of p25 and increased Cdk5 activity, which can exacerbate inflammatory responses to a pro-inflammatory state in glial cells of
AD-related pathogenesis (Hsiao et al., 2011; Huang et al., 2015). The the hippocampus. Interestingly, acute 5-day isolation at 6–8 weeks of
expression of p25 further contributes to the cytoskeletal disruptions age is sufficient to lead to increased neuroinflammation in the hippo
along with an increase in tau hyperphosphorylation (Tseng et al., 2002). campus of male Wistar rats, which show enhanced expression of in
Calpain or proteasome inhibitors prevent the isolation-induced deficits flammatory cytokines (IL-6, TNF α) (Alshammari et al., 2020). The
in pathology and behavior, bringing additional insight into the mecha inflammatory changes were also observed in male control and AlCl3 rat
nisms and potential prevention strategies (Hsiao et al., 2011). Alto model of AD after chronic 4-week social isolation (Ali et al., 2017).
gether, the mechanisms contributing to the detrimental effects of post-
weaning social isolation in AD animal models seem to include in part, 3.2.3. Stress and the HPA axis
increased p25/p35 ratio, along with increased calpain and cdk5 activity, A strong mediator regulating impairments in cognitive performance
leading to tau hyperphosphorylation and severe neurodegeneration. The is stress-induced cortisol dysregulation, which has been reported in
cause of increased tau hyperphosphorylation as a result of social isola patients with AD (Drinkwater et al., 2022; Ouanes and Popp, 2019). The
tion have also been attributed to additional mechanisms independent of critical role of the hippocampus in the regulation of the HPA axis (Eliwa
Aβ accumulation. Social isolation can lead to the dysregulation of the et al., 2021) and the vulnerability of this region in AD may lead to the
two isoforms of glycogen synthase kinase 3 (GSK3), that contributes to chicken and egg scenario of a hippocampal deficit leading to cortisol
abnormal tau phosphorylation (Hanger et al., 1992; Mandelkow et al., dysregulation and increased cortisol causing more damage in this region
1992). In socially isolated male senescence accelerated mouse (SAMP8) (Ennis et al., 2017). Similar to humans, social isolation is stressful for
14
social animals, and can have long-lasting effects especially if isolation Social housing has also been shown to provide neuroprotective effects in
starts during a critical developmental time window (Lander et al., 2017). AD animal models. After being co-housed with wild-type mice, male
Social isolation leads to a dysregulation in plasma corticosterone levels APP/PS1 mice show improved spatial memory along with increased
in rodents isolated right after weaning, with increased levels detected in hippocampal brain-derived neurotrophic factor (BDNF) levels and
female and male mice isolated for 24 weeks, and reduced levels in rats neurogenesis (Hsiao et al., 2014). These effects are greater when mice
isolated for 8 weeks (Harvey et al., 2019) (but also see: no difference in are grouped in five, as opposed to the isolated or paired animals.
stress-induced cortisol levels in O. degus isolated for 6.5 months in Improved cognitive function in group-housed animals is associated with
adulthood (Pereda-Pérez et al., 2013)). The differences in corticosterone enhanced hippocampus dependent synaptic transmission, astrocytic
levels can possibly be ascribed to the methodological differences of so response and transition of microglia from a pro-inflammatory to an anti-
cial isolation rearing, including housing conditions, duration and period inflammatory state, without an effect on amyloid plaque deposition
of isolation and animal strain (Regenass et al., 2018). In post-weaning (Liang et al., 2019). In contrast to the detrimental effects of social
isolated rats, dysregulation of the HPA axis has been commonly impli isolation on cognition, social interaction may therefore prevent cogni
cated with a failure to modulate corticosterone levels in response to tive deficits and AD-related pathology, further strengthening the
acute stress (Butler et al., 2014; Lukkes et al., 2009a; Pisu et al., 2016). requirement for social intervention strategies during preclinical stages
Additionally, sexual dimorphic hormone responses were identified in of AD.
some studies, showing decreased plasma corticosterone levels in isolated
male rats while females tended to have higher corticosterone levels, 3.4. Summary
when compared with group-housed animals. This may reflect differen
tial vulnerabilities in females and males to stress, particularly within the Taken together, animal models of social isolation provide significant
context of social stress (Harvey et al., 2019; Regenass et al., 2018). In insight into the underlying mechanisms for isolation-induced cognitive
studies of animal models of AD, 9-month-old 3xTg female mice show an impairments. Accordingly, social isolation in animal models of AD has
elevated corticosteroid response following stressful tasks (e.g. after 5 been associated with increased amyloid plaque deposition, neurofibril
days of MWM training), which consequently affects cognitive perfor lary tangles, neuroinflammation and altered hormonal stress responses.
mance, compared to the age-matched 3xTg males (Clinton et al., 2007). This can go hand in hand with the functionally and structurally
Interestingly, the dysregulation of the HPA axis occurs much earlier in remodeled hippocampus, as well as behavioral deficits (Huang et al.,
the TgCRND8 male mice than in TgCRND8 females (Touma et al., 2004). 2015), including impairments in spatial learning and memory, object
These interesting observations highlight the need for more research recognition memory, fear memory but also increased anxiety-like be
focused on the identification of the mechanisms underlying the sexual haviors. Numerous studies in animal models of AD show that chronic
dimorphism in hormone responses to stress (e.g. social isolation) in isolation stress increases Aβ levels via enhancing β/γ-secretase activity,
animal models of AD. exacerbates hyperphosphorylation of tau via increasing the conversion
of p35 to p25, which further facilitates the progression of dementia and
3.3. Enriched environment as a protective factor for dementia and AD AD via stimulation of inflammasome activation and altering HPA axis.
These changes can contribute to the accelerated cell apoptosis (Ali et al.,
Enriched housing provides a means of increased sensory stimulation 2017; Cao et al., 2018), decreased synaptic activity (Huang et al., 2015;
for animals, especially when compared with the monotonous and lonely Rivera et al., 2020; Tamano et al., 2016), impaired LTP (Hsiao et al.,
environment of isolation housing. Enriched environment includes 2012, 2011; Joshi et al., 2014), along with aberrant morphological
physical enrichment, such as running wheels, larger cages, toys, and changes and synaptic plasticity (Gong et al., 2017).
novel objects (Pietropaolo et al., 2004; Smith et al., 2017), which pro Enriched housing creates a stimulating environment that promotes
vides sensorial and visual stimulations, and the ability to exercise. There the development of cognitive, motor, sensory and social abilities in ro
is substantial evidence supporting the beneficial effects of enriched dents (Fischer, 2016). Providing an enriched environment and social
housing on isolated animals, however, the efficacy remains somewhat housing for rodent models of AD confers protection against the rapid
limited. In socially isolated male APP/PS1 mice (isolated at PND 28 for cognitive decline typically observed in isolated animals (Cao et al.,
8 weeks), access to physical enrichment leads to a greater spatial 2018; Hsiao et al., 2014). While physical enrichment alone may not fully
memory performance in the MWM and Y-maze tests, compared with the alleviate the cognitive deficits in older mice (Peterman et al., 2020),
isolated mice raised under standard environment conditions (Cao et al., social housing has been sufficient to effectively enhance cognition at
2018). AD-related pathological changes are also prevented by exposure advanced stages of memory impairment (Hsiao et al., 2014). These
to enriched housing. In isolated APP/PS1 mice, both cellular apoptosis beneficial effects of enrichment have been attributed to decreased
and synaptic loss in the hippocampus exacerbated by social isolation inflammation (Liang et al., 2019), increased synaptic transmission (Cao
have been alleviated by enriched housing. These effects have been et al., 2018; Liang et al., 2019), and neurogenesis (Hsiao et al., 2014).
attributed in part to enrichment-induced decrease in inflammatory Further research focused on how isolation-induced changes in the brain
markers, astrocyte activation and increase in experience-dependent contribute to dysfunctional circuits in AD and how social housing can
synaptogenesis (Cao et al., 2018). In contrast, in male 5xFAD mice prevent or improve these deficits is crucial for the development of new
(isolated at 2 months for 2–3 months), enriched environment failed to treatment strategies.
prevent the isolation-induced increase in cognitive deficits and accel
eration in hippocampal Aβ plaque formation (Peterman et al., 2020). As 4. Gender and sex differences
the effects of isolation and housing on the inflammation and the HPA
axis activation remain to be determined in this study, exposure to the Social isolation and loneliness affect brain function and mental
enriched environment at an older age (2 months old) may be ineffective health differentially in women and men (Di Marco et al., 2014; Zeb
in preventing a degenerative process that has already been initiated. hauser et al., 2014; Zhou et al., 2018) with some exceptions (Evans et al.,
Social housing from an early age enables social interactions (crawl 2019; Montoliu et al., 2019; Wang et al., 2020; Yu et al., 2021) (Table 3).
ing over one another, allogrooming, huddling, sniffing, following) It has been robustly reported that older women are more likely living
which are integral to the establishment of proper social functioning alone and are more inclined to feel lonely compared to older men
during adulthood (Kondrakiewicz et al., 2019). Similar to the effects of (Akhter-Khan et al., 2021; Holwerda et al., 2012; Zebhauser et al.,
the physical enrichment provided with enriched housing, social housing 2014). Overall, women have been reported to have a higher incidence of
alleviates the isolation-induced deficits in hippocampus-dependent cognitive decline (Fratiglioni et al., 2000; Sörman et al., 2015;
spatial learning, synaptic function and neurogenesis (Lu et al., 2003). Sundström et al., 2020; Wang et al., 2020) and experience a faster
15
Table 3
Gender/Sex differences in clinical studies.
Sample Size Sex/Gender differences in isolation/ Sex/Gender differences in Sex/Gender differences in the Original
loneliness cognition/mental health status relationship between isolation/ Publication
loneliness and dementia
Total: 1203 NA Incidence rate of dementia NA Fratiglioni et al.

F: 897 M: 37.0 (2000)
M: 306 F: 56.5
Females: higher dementia
incidence
Total: 823 NA NA NA Wilson et al.
F: 75.7 % (2007)
Baseline: NA Incidence of dementia data: NA Lobo et al. (2008)
F: 2771 Baseline:
M: 2032 M: 42.31
Follow-up: F:1792 F: 57.69
M:1452 Two years later:
M: 44.76
F: 55.24
Total: 2089 NA NA NA Amieva et al.
F: 1251 (2010)
M: 838
Total: 466 NA NA NA O’Luanaigh et al.
F: 258 (2012)
M: 208
Total: 6034 Isolation: no sex difference NA NA Shankar et al.
M: 45.3 % Females: higher loneliness (2013)
Total: 2173 NA No difference between males and NA Holwerda et al.
F: 1372 females in developing dementia. (2014)
M: 801 F: 7.6 %
M: 6.7 %
Total: 1715 NA All-cause dementia or AD: higher NA Sörman et al.
F: 958 proportion of women (2015)
M: 757 F: 65.1 % (all cause dementia),
73.9 % (AD)
Total: 8382 F: more likely feel lonely NA NA Donovan et al.
M: 40 % M: 30 % (lonely) (2017)
Total: 779 NA NA NA Poey et al. (2017)
F: 452
M: 327
Total: 1601 NA NA NA Rawtaer et al.
F: 1033 No gender differences in the effect of marital (2017)
M: 568 status on incident MCI-dementia.
Total: 14,199 for analyses, NA NA NA Zhong et al.
M: 44.26 % (2017)
Total: 93 NA No sex differences NA Balouch et al.
F: 51 (2019)
M: 42
Total: 345 F: higher level of baseline loneliness NA NA Grande et al.
F: 56 % (2018)
Total: 7867 NA NA F: weak relationship between loneliness and Zhou et al. (2018)
F: 4316 dementia
M: 3551 M: lonely men are more likely to suffer from
mental health problems
Baseline: F: more women living alone at baseline; No sex differences No sex differences Evans et al.
F: 1112 70.19 % (2019)
M:1085 M: 29.81 %
Follow-up: F: 751
M: 747
Total: 86 No sex difference in loneliness NA No sex difference in the association between Montoliu et al.
F: 45 loneliness and cognitive function (2019)
M: 41
Baseline: 8780 F: higher level of baseline loneliness, NA No sex differences Yin et al. (2019)
M: 44.6 % poorer performance in memory at
Total for analysis: 5885 baseline
Total: 6654 NA F: higher incidence of cognitive NA Griffin et al.
F: 6026 impairment (2020)
M: 4350
Total: 378 NA No sex difference in cognitive NA Kuiper et al.
F: 250 performance (2020)
M: 128
Total: 14,114 NA No sex differences No sex differences Luchetti et al.
F: 54.7 % (2020)
M: 45.3 %
Total: 6677 NA NA NA Rafnsson et al.
F: 3716 (2020)
M: 2961
16
Sample Size Sex/Gender differences in isolation/ Sex/Gender differences in Sex/Gender differences in the Original
loneliness cognition/mental health status relationship between isolation/ Publication
loneliness and dementia
Total: 1477 NA F: higher incidence of all cause NA Sundström et al.

F: 777 dementia, AD, VaD (2020)
M: 700
Total: 12,030 NA No sex difference in cognitive NA Sutin et al.
F: 60 % status (2020)
Total: 713 NA F: faster cognitive decline No sex differences Wang et al.
F: 71 % (2020)
Total: 2880 Subjects who reported loneliness were NA NA Akhter-Khan
M: 1328 more likely to be female et al. (2021)
F: 1552
Total: 18,328 (cognitively NA No sex differences NA Giné-Garriga
impaired cohort at wave 5), et al. (2021)
F: 9674
M: 8654
Total: 617 NA NA NA Pugh et al. (2021)
F: 77 %
19,092 middle-aged; 13,623 NA NA NA Smith et al.
older adults (2021)
M and F % differs based on
different countries and age
Total: 7761, No sex differences No sex difference in episodic No sex differences Yu et al. (2021)
M: 50.8 % memory
Sex difference in mental status
Total: 155,070 NA NA No interaction between sex and isolation or Elovainio et al.
F: 51.9 % sex and loneliness predicting dementia risk (2022)
Total: 4514 NA No sex differences NA Freak-Poli et al.
M: 2048 (2022)
F: 2739
Total: 2308 NA NA NA Salinas et al.
F: 56 % (2022)
Total: 462,619 NA NA NA Shen et al. (2022)
M: 209,975
F: 252,644
AD, Alzheimer’s Disease; F, Female; M, male; NA, not available; VaD, vascular dementia.
cognitive decline than men (Wang et al., 2020; Zhou et al., 2018). only provide insight into sex-dependent effects on social isolation-
However, men who experience loneliness are more likely to suffer from induced deficits and AD pathologies, but will also help to develop sex-
mental health problems (Zebhauser et al., 2014) although the mecha specific intervention and treatment strategies. The long-term effects of
nisms remain unknown. The different stress responses between women postweaning social isolation on the behavior of female and male animals
and men and/or greater vulnerability to loneliness in women may have been reported (Fone and Porkess, 2008). In animal models of AD,
contribute to the observed gender differences in the relationship be female mice are consistently susceptible to AD and exhibit greater
tween loneliness and cognitive impairment in different genders. Sex cognitive decline than males (Devi et al., 2010), which is consistent with
dimorphism of hormone secretion, inflammation reaction and bio- the clinical studies. For example, compared to isolated 3xTg males, the
behavioral mechanisms have also been proposed to be some of the hippocampal Aβ pathology is exacerbated in socially isolated female
likely underlying causes (Zhou et al., 2018). 3xTg mice (Pietropaolo et al., 2009). Compared to the isolated male
While some studies found subtle effects, others reported more pro wild-type rats, female wild-type rats are more sensitive to social isola
nounced effects of loneliness in females (Walker et al., 2019) or males tion showing greater impairment in social recognition memory (Shahar-
(Zhou et al., 2018). This discrepancy can be in part due to the far less Gold et al., 2013). Social isolation starting in early adulthood (e.g. 2
studies focused on gender/sex differences on the relationship between months old) leads to cognitive deficits in hippocampus-dependent
loneliness and mental health. Even though both genders are included in contextual fear conditioning in male wild-type and 5xFAD mice
the majority of human studies and sex differences have already been (Peterman et al., 2020). While late-life isolation in 18-month-old
identified in loneliness (Donovan et al., 2017; Holwerda et al., 2012; C57BL/6xSV129 mice does not affect hippocampus-related fear
Zebhauser et al., 2014) and cognitive decline (Fratiglioni et al., 2000; learning and memory in females (Sullens et al., 2021).
Sörman et al., 2015), only a few studies analyzed sex differences in the Among the preclinical studies summarized in Table 2, 4 out of 15
association between loneliness and cognitive decline (Evans et al., 2019; (26.67 %) included both sexes and only one (6.67 %) evaluated sex
Luchetti et al., 2020; Montoliu et al., 2019; Zhou et al., 2018). According differences. Behavioral studies in male-only animal models (10 studies/
to the studies summarized in Table 3, despite the majority of them 66.67 %) significantly outnumber those using only females (1 study/
included both sexes and used sex as a variable in the analysis, fourteen 6.67 %), despite the increased incidence of stress susceptibility (Hodes
studies (41.2 %) analyzed sex differences in mental health, eight studies and Epperson, 2019) and dementia in women (Mielke, 2018). As a
(23.5 %) evaluated sex differences in isolation/loneliness and nine result, there is a significant ambiguity in understanding the neural
studies (26.5 %) assessed the sex difference in the relationship between mechanisms underlying disease susceptibility and/or treatment and
isolation/loneliness and cognitive function or dementia. Keeping in intervention strategies for different sexes.
mind the potential sex dimorphic effects on loneliness induced cognitive
impairments, further investigating the sex differences in this association 5. Conclusion and future directions
will lead to a better understanding of the underlying mechanisms.
In preclinical studies using animal models, it is extremely important Taken together, clinical studies suggest a strong correlation between
to highlight the differences between males and females, which will not loneliness and cognitive performance (Table 1), and to a lesser extent,
17
between loneliness and the AD-related pathological changes (d’Oleire Acknowledgements

Uquillas et al., 2018; Donovan et al., 2016). Despite numerous studies
showing this association, the underlying mechanisms remain unclear. Funding for this study was provided by an Alzheimer’s Association
The baseline levels of cognition (Balouch et al., 2019) or psychological Grant (AARG-22-917644) in partnership with Brain Canada to DS, an
illness (Kuiper et al., 2020), age (Smith et al., 2021), race (Pugh et al., Alzheimer’s Society Research Program (ASRP) New Investigator Grant
2021) and sex (Table 3) are among the many factors that have signifi (#21-05) to JRE. YR received a graduate fellowship from the Hotchkiss
cant influence in the outcome of these studies. Clinical studies therefore Brain Institute. SP received an Undergraduate Research Award from
need to consider numerous covariates, including but not limited to age, NSERC (NSERC-USRA). AS received an undergraduate research fellow
education, race, ethnicity, marital status, employment status, disease ship from the Hotchkiss Brain Institute.
stage which altogether strengthens the power of the analysis (Kahan
et al., 2014). Yet, the presence of unidentified genetic or environmental References
factors may add to the heterogeneity of the human population, making
the interpretation of the results more challenging. Additionally, the Akhter-Khan, S.C., Tao, Q., Ang, T.F.A., Itchapurapu, I.S., Alosco, M.L., Mez, J., Piers, R.
J., Steffens, D.C., Au, R., Qiu, W.Q., 2021. Associations of loneliness with risk of
limitation of the available methodologies makes it difficult to decipher Alzheimer’s disease dementia in the Framingham Heart Study. Alzheimers. Dement.
the underlying causes for the observed differences. Recent imaging 17, 1619–1627. https://doi.org/10.1002/alz.12327.
technologies identified pathological changes reminiscent of the AD pa Ali, A.A., Khalil, M.G., Elariny, H.A., Abu-Elfotuh, K., 2017. Study on social isolation as a
risk factor in development of Alzheimer’s disease in rats. Brain Disord. Ther. 6, 2.
thology in the brains of lonely individuals. Importantly, loneliness- Alshammari, T.K., Alghamdi, H., Alkhader, L.F., Alqahtani, Q., Alrasheed, N.M.,
induced increase in cortical amyloid deposition and tau pathology in Yacoub, H., Alnaem, N., AlNakiyah, M., Alshammari, M.A., 2020. Analysis of the
the absence of cognitive decline (Biddle et al., 2019; d’Oleire Uquillas molecular and behavioral effects of acute social isolation on rats. Behav. Brain Res.
377, 112191 https://doi.org/10.1016/j.bbr.2019.112191.
et al., 2018; Donovan et al., 2016) or differences in brain volume in the Amieva, H., Stoykova, R., Matharan, F., Helmer, C., Antonucci, T.C., Dartigues, J.-F.,
early stages of AD (Zhang et al., 2022b) and in dementia-free high-risk 2010. What aspects of social network are protective for dementia? Not the quantity
lonely individuals (Salinas et al., 2022) indicated the presence of pa but the quality of social interactions is protective up to 15 years later. Psychosom.
Med. 72, 905–911. https://doi.org/10.1097/PSY.0b013e3181f5e121.
thology prior to the clinical diagnosis of dementia. These studies suggest
Arakawa, H., 2018. Ethological approach to social isolation effects in behavioral studies
that loneliness could exacerbate cognitive decline by contributing to the of laboratory rodents. Behav. Brain Res. 341, 98–108. https://doi.org/10.1016/j.
pathology prior to or in the early stages of the disease, emphasizing the bbr.2017.12.022.
importance of early interventions and the urgency to determine the Arem, H., Moore, S.C., Patel, A., Hartge, P., Berrington de Gonzalez, A., Visvanathan, K.,
Campbell, P.T., Freedman, M., Weiderpass, E., Adami, H.O., Linet, M.S., Lee, I.-M.,
underlying mechanisms. Matthews, C.E., 2015. Leisure time physical activity and mortality: a detailed pooled
Based on the observed studies included in this review, the majority of analysis of the dose-response relationship. JAMA Intern. Med. 175, 959–967.
the potential mechanisms underlying the association between loneliness https://doi.org/10.1001/jamainternmed.2015.0533.
Balouch, S., Rifaat, E., Chen, H.L., Tabet, N., 2019. Social networks and loneliness in
and dementia have been attributed to the changes in the HPA axis, people with Alzheimer’s dementia. Int. J. Geriatr. Psychiatry 34, 666–673. https://
neuroinflammatory markers and/or affected by the cognitive reserve doi.org/10.1002/gps.5065.
hypothesis. These questions and further mechanisms can be more Baumeister, R.F., Leary, M.R., 1995. The need to belong: desire for interpersonal
attachments as a fundamental human motivation. Psychol. Bull. 117, 497–529.
thoroughly investigated using the relevant animal models. Preclinical https://doi.org/10.1037/0033-2909.117.3.497.
models provide valuable insight into the mechanisms underlying the risk Bennett, D.A., Schneider, J.A., Tang, Y., Arnold, S.E., Wilson, R.S., 2006. The effect of
factors for dementia and open revenues for potential prevention stra social networks on the relation between Alzheimer’s disease pathology and level of
cognitive function in old people: a longitudinal cohort study. Lancet Neurol. 5,
tegies. However, despite the vast amount of research that studied al 406–412. https://doi.org/10.1016/S1474-4422(06)70417-3.
terations in pathology and behavior in animal models of social isolation Beutel, M.E., Klein, E.M., Brähler, E., Reiner, I., Jünger, C., Michal, M., Wiltink, J.,
and AD, few of these focused on both sexes. As a result, there is signif Wild, P.S., Münzel, T., Lackner, K.J., Tibubos, A.N., 2017. Loneliness in the general
population: prevalence, determinants and relations to mental health. BMC
icant ambiguity in understanding the neural mechanisms of the social
Psychiatry 17, 97. https://doi.org/10.1186/s12888-017-1262-x.
isolation in females. These issues necessitate more studies that include Bhatti, A.B., Haq, A.U., 2017. The Pathophysiology of Perceived Social Isolation: Effects
both sexes and using sex as a main factor in the analysis. on Health and Mortality. Cureus 9, e994.
Finally, in order to understand the mechanisms underlying the risk Bicks, L.K., Yamamuro, K., Flanigan, M.E., Kim, J.M., Kato, D., Lucas, E.K., Koike, H.,
Peng, M.S., Brady, D.M., Chandrasekaran, S., Norman, K.J., Smith, M.R., Clem, R.L.,
factors for dementia, the studies will need to focus on brain-wide al Russo, S.J., Akbarian, S., Morishita, H., 2020. Prefrontal parvalbumin interneurons
terations rather than discrete changes in specific brain regions. The require juvenile social experience to establish adult social behavior. Nat. Commun.
majority of social isolation studies in AD animals focus on hippocampus, 11, 1–15. https://doi.org/10.1038/s41467-020-14740-z.
Biddle, K.D., d’Oleire Uquillas, F., Jacobs, H.I.L., Zide, B., Kirn, D.R., Rentz, D.M.,
a critical brain region for learning and memory. In contrast, AD-specific Johnson, K.A., Sperling, R.A., Donovan, N.J., 2019. Social Engagement and Amyloid-
pathologies are known to spread from the entorhinal cortex, a major β-Related Cognitive Decline in Cognitively Normal Older Adults. Am. J. Geriatr.
input and output structure of the hippocampal formation, to the parietal Psychiatry 27, 1247–1256. https://doi.org/10.1016/j.jagp.2019.05.005.
Boss, L., Kang, D.-H., Branson, S., 2015. Loneliness and cognitive function in the older
cortex and other cortical regions, contributing both directly and indi adult: a systematic review. Int. Psychogeriatr. 27, 541–553. https://doi.org/
rectly to cognitive loss (Khan et al., 2014; Olajide et al., 2021). There 10.1017/S1041610214002749.
fore, based on current findings, further in-depth investigations into the Bruscoli, M., Lovestone, S., 2004. Is MCI really just early dementia? A systematic review
of conversion studies. Int. Psychogeriatr. 16, 129–140. https://doi.org/10.1017/
other brain regions and circuits will give us a better understanding on s1041610204000092.
the influence of social isolation in AD. Butler, T.R., Ariwodola, O.J., Weiner, J.L., 2014. The impact of social isolation on HPA
axis function, anxiety-like behaviors, and ethanol drinking. Front. Integr. Neurosci.
7, 102. https://doi.org/10.3389/fnint.2013.00102.
Declaration of Competing Interest
Cacioppo, S., Capitanio, J.P., Cacioppo, J.T., 2014. Toward a neurology of loneliness.
Psychol. Bull. 140, 1464–1504. https://doi.org/10.1037/a0037618.
The authors declare that they have no known competing financial Cacioppo, J.T., Hawkley, L.C., 2009. Perceived social isolation and cognition. Trends
interests or personal relationships that could have appeared to influence Cogn. Sci. 13, 447–454. https://doi.org/10.1016/j.tics.2009.06.005.
Cacioppo, J.T., Hughes, M.E., Waite, L.J., Hawkley, L.C., Thisted, R.A., 2006. Loneliness
the work reported in this paper. as a specific risk factor for depressive symptoms: cross-sectional and longitudinal
analyses. Psychol. Aging 21, 140–151. https://doi.org/10.1037/0882-
Data availability 7974.21.1.140.
Cacioppo, J.T., Hawkley, L.C., Thisted, R.A., 2010. Perceived social isolation makes me
sad: 5-year cross-lagged analyses of loneliness and depressive symptomatology in the
No data was used for the research described in the article. Chicago Health, Aging, and Social Relations Study. Psychol. Aging 25, 453–463.
https://doi.org/10.1037/a0017216.
Canli, T., Yu, L., Yu, X., Zhao, H., Fleischman, D., Wilson, R.S., De Jager, P.L., Bennett, D.
A., 2018. Loneliness 5 years ante-mortem is associated with disease-related
18
differential gene expression in postmortem dorsolateral prefrontal cortex. Transl. Fone, K.C.F., Porkess, M.V., 2008. Behavioural and neurochemical effects of post-
Psychiatry 8, 2. https://doi.org/10.1038/s41398-017-0086-2. weaning social isolation in rodents-relevance to developmental neuropsychiatric
Cao, M., Hu, P.-P., Zhang, Y.-L., Yan, Y.-X., Shields, C.B., Zhang, Y.-P., Hu, G., Xiao, M., disorders. Neurosci. Biobehav. Rev. 32, 1087–1102. https://doi.org/10.1016/j.
2018. Enriched physical environment reverses spatial cognitive impairment of neubiorev.2008.03.003.
socially isolated APPswe/PS1dE9 transgenic mice before amyloidosis onset. CNS Ford, E.S., Loucks, E.B., Berkman, L.F., 2006. Social integration and concentrations of C-
Neurosci. Therapeutics 24 (3), 202–211. reactive protein among US adults. Ann. Epidemiol. 16, 78–84. https://doi.org/
Cho, J.-H.-J., Olmstead, R., Choi, H., Carrillo, C., Seeman, T.E., Irwin, M.R., 2019. 10.1016/j.annepidem.2005.08.005.
Associations of objective versus subjective social isolation with sleep disturbance, Fratiglioni, L., Wang, H.X., Ericsson, K., Maytan, M., Winblad, B., 2000. Influence of
depression, and fatigue in community-dwelling older adults. Aging Ment. Health 23, social network on occurrence of dementia: a community-based longitudinal study.
1130–1138. https://doi.org/10.1080/13607863.2018.1481928. Lancet 355, 1315–1319. https://doi.org/10.1016/S0140-6736(00)02113-9.
Clinton, L.K., Billings, L.M., Green, K.N., Caccamo, A., Ngo, J., Oddo, S., McGaugh, J.L., Freak-Poli, R., Wagemaker, N., Wang, R., Lysen, T.S., Ikram, M.A., Vernooij, M.W.,
LaFerla, F.M., 2007. Age-dependent sexual dimorphism in cognition and stress Dintica, C.S., Vernooij-Dassen, M., Melis, R.J.F., Laukka, E.J., Fratiglioni, L., Xu, W.,
response in the 3xTg-AD mice. Neurobiol. Dis. 28, 76–82. https://doi.org/10.1016/j. Tiemeier, H., 2022. Loneliness, Not Social Support, Is Associated with Cognitive
nbd.2007.06.013. Decline and Dementia Across Two Longitudinal Population-Based Cohorts.
Conrad, C.D., Bimonte-Nelson, H.A., 2010. Impact of the hypothalamic-pituitary- J. Alzheimers. Dis. 85, 295–308. https://doi.org/10.3233/JAD-210330.
adrenal/gonadal axes on trajectory of age-related cognitive decline. Prog. Brain Res. Gellert, P., Häusler, A., Suhr, R., Gholami, M., Rapp, M., Kuhlmey, A., Nordheim, J.,
182, 31–76. https://doi.org/10.1016/S0079-6123(10)82002-3. Firmino, H., 2018. Testing the stress-buffering hypothesis of social support in
Cornwell, E.Y., Waite, L.J., 2009. Measuring social isolation among older adults using couples coping with early-stage dementia. PLoS One 13 (1), e0189849.
multiple indicators from the NSHAP study. J. Gerontol. B Psychol. Sci. Soc. Sci. 64 Giné-Garriga, M., Jerez-Roig, J., Coll-Planas, L., Skelton, D.A., Inzitari, M., Booth, J.,
Suppl 1, i38–i46. https://doi.org/10.1093/geronb/gbp037. Souza, D.L.B., 2021. Is loneliness a predictor of the modern geriatric giants? Analysis
Coyle, C.E., Dugan, E., 2012. Social isolation, loneliness and health among older adults. from the survey of health, ageing, and retirement in Europe. Maturitas 144, 93–101.
J. Aging Health 24, 1346–1363. https://doi.org/10.1177/0898264312460275. https://doi.org/10.1016/j.maturitas.2020.11.010.
Creecy, R.F., Berg, W.E., Wright Jr, R., 1985. Loneliness among the elderly: a causal Glenner, G.G., Wong, C.W., 1984. Alzheimer’s disease: initial report of the purification
approach. J. Gerontol. 40, 487–493. https://doi.org/10.1093/geronj/40.4.487. and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys.
Crooks, V.C., Lubben, J., Petitti, D.B., Little, D., Chiu, V., 2008. Social network, cognitive Res. Commun. 120, 885–890. https://doi.org/10.1016/s0006-291x(84)80190-4.
function, and dementia incidence among elderly women. Am. J. Public Health 98, Golaszewski, N.M., LaCroix, A.Z., Godino, J.G., Allison, M.A., Manson, J.E., King, J.J.,
1221–1227. https://doi.org/10.2105/AJPH.2007.115923. Weitlauf, J.C., Bea, J.W., Garcia, L., Kroenke, C.H., Saquib, N., Cannell, B.,
d’Oleire Uquillas, F., Jacobs, H.I.L., Biddle, K.D., Properzi, M., Hanseeuw, B., Schultz, A. Nguyen, S., Bellettiere, J., 2022. Evaluation of social isolation, loneliness, and
P., Rentz, D.M., Johnson, K.A., Sperling, R.A., Donovan, N.J., 2018. Regional tau cardiovascular disease among older women in the US. JAMA Netw. Open 5 (2),
pathology and loneliness in cognitively normal older adults. Transl. Psychiatry 8, e2146461.
282. https://doi.org/10.1038/s41398-018-0345-x. Gong, W.-G., Wang, Y.-J., Zhou, H., Li, X.-L., Bai, F., Ren, Q.-G., Zhang, Z.-J., 2017.
Devi, L., Alldred, M.J., Ginsberg, S.D., Ohno, M., 2010. Sex- and brain region-specific Citalopram Ameliorates Synaptic Plasticity Deficits in Different Cognition-Associated
acceleration of β-amyloidogenesis following behavioral stress in a mouse model of Brain Regions Induced by Social Isolation in Middle-Aged Rats. Mol. Neurobiol. 54,
Alzheimer’s disease. Mol. Brain 3, 34. https://doi.org/10.1186/1756-6606-3-34. 1927–1938. https://doi.org/10.1007/s12035-016-9781-x.
Di Marco, L.Y., Marzo, A., Muñoz-Ruiz, M., Ikram, M.A., Kivipelto, M., Ruefenacht, D., Grande, G., Vetrano, D.L., Cova, I., Pomati, S., Mattavelli, D., Maggiore, L., Cucumo, V.,
Venneri, A., Soininen, H., Wanke, I., Ventikos, Y.A., Frangi, A.F., 2014. Modifiable Ghiretti, R., Vanacore, N., Mariani, C., Rizzuto, D., 2018. Living Alone and Dementia
lifestyle factors in dementia: a systematic review of longitudinal observational Incidence: A Clinical-Based Study in People With Mild Cognitive Impairment.
cohort studies. J. Alzheimers. Dis. 42, 119–135. https://doi.org/10.3233/JAD- J. Geriatr. Psychiatry Neurol. 31, 107–113. https://doi.org/10.1177/
132225. 0891988718774425.
Dong, H., Goico, B., Martin, M., Csernansky, C.A., Bertchume, A., Csernansky, J.G., 2004. Griffin, S.C., Mezuk, B., Williams, A.B., Perrin, P.B., Rybarczyk, B.D., 2020. Isolation, Not
Modulation of hippocampal cell proliferation, memory, and amyloid plaque Loneliness or Cynical Hostility, Predicts Cognitive Decline in Older Americans.
deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127, J. Aging Health 32, 52–60. https://doi.org/10.1177/0898264318800587.
601–609. https://doi.org/10.1016/j.neuroscience.2004.05.040. Grundke-Iqbal, I., Iqbal, K., Tung, Y.C., Quinlan, M., Wisniewski, H.M., Binder, L.I.,
Dong, H., Yuede, C.M., Yoo, H.-S., Martin, M.V., Deal, C., Mace, A.G., Csernansky, J.G., 1986. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in
2008. Corticosterone and related receptor expression are associated with increased Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U. S. A. 83, 4913–4917.
beta-amyloid plaques in isolated Tg2576 mice. Neuroscience 155, 154–163. https:// https://doi.org/10.1073/pnas.83.13.4913.
doi.org/10.1016/j.neuroscience.2008.05.017. Gunnar, M.R., Hostinar, C.E., 2015. The social buffering of the hypothalamic-pituitary-
Donovan, N.J., Okereke, O.I., Vannini, P., Amariglio, R.E., Rentz, D.M., Marshall, G.A., adrenocortical axis in humans: Developmental and experiential determinants. Soc.
Johnson, K.A., Sperling, R.A., 2016. Association of Higher Cortical Amyloid Burden Neurosci. 10, 479–488. https://doi.org/10.1080/17470919.2015.1070747.
With Loneliness in Cognitively Normal Older Adults. JAMA Psychiatry 73, Hackett, R.A., Steptoe, A., Cadar, D., Fancourt, D., Bayer, A., 2019. Social engagement
1230–1237. https://doi.org/10.1001/jamapsychiatry.2016.2657. before and after dementia diagnosis in the English longitudinal study of ageing. PLoS
Donovan, N.J., Wu, Q., Rentz, D.M., Sperling, R.A., Marshall, G.A., Glymour, M.M., One 14 (8), e0220195.
2017. Loneliness, depression and cognitive function in older U.S. adults. Int. J. Hanger, D.P., Hughes, K., Woodgett, J.R., Brion, J.-P., Anderton, B.H., 1992. Glycogen
Geriatr. Psychiatry 32, 564–573. https://doi.org/10.1002/gps.4495. synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau:
Drinkwater, E., Davies, C., Spires-Jones, T.L., 2022. Potential neurobiological links Generation of paired helical filament epitopes and neuronal localisation of the
between social isolation and Alzheimer’s disease risk. Eur. J. Neurosci. 56, kinase. Neurosci. Lett. 147, 58–62. https://doi.org/10.1016/0304-3940(92)90774-
5397–5412. https://doi.org/10.1111/ejn.15373. 2.
Du Preez, A., Law, T., Onorato, D., Lim, Y.M., Eiben, P., Musaelyan, K., Egeland, M., Harvey, B.H., Regenass, W., Dreyer, W., Möller, M., 2019. Social isolation rearing-
Hye, A., Zunszain, P.A., Thuret, S., Pariante, C.M., Fernandes, C., 2020. The type of induced anxiety and response to agomelatine in male and female rats: Role of
stress matters: repeated injection and permanent social isolation stress in male mice corticosterone, oxytocin, and vasopressin. J. Psychopharmacol. 33, 640–646.
have a differential effect on anxiety- and depressive-like behaviours, and associated https://doi.org/10.1177/0269881119826783.
biological alterations. Transl. Psychiatry 10, 1–17. https://doi.org/10.1038/s41398- Hawkley, L.C., Cacioppo, J.T., 2010. Loneliness matters: a theoretical and empirical
020-01000-3. review of consequences and mechanisms. Ann. Behav. Med. 40, 218–227. https://
Eliwa, H., Brizard, B., Le Guisquet, A.-M., Hen, R., Belzung, C., Surget, A., 2021. Adult doi.org/10.1007/s12160-010-9210-8.
neurogenesis augmentation attenuates anhedonia and HPA axis dysregulation in a Hawkley, L.C., Preacher, K.J., Cacioppo, J.T., 2010. Loneliness impairs daytime
mouse model of chronic stress and depression. Psychoneuroendocrinology 124, functioning but not sleep duration. Health Psychol. 29, 124–129. https://doi.org/
105097. https://doi.org/10.1016/j.psyneuen.2020.105097. 10.1037/a0018646.
Elovainio, M., Lahti, J., Pirinen, M., Pulkki-Råback, L., Malmberg, A., Lipsanen, J., Hawthorne, G., 2008. Perceived social isolation in a community sample: its prevalence
Virtanen, M., Kivimäki, M., Hakulinen, C., 2022. Association of social isolation, and correlates with aspects of peoples’ lives. Soc. Psychiatry Psychiatr. Epidemiol.
loneliness and genetic risk with incidence of dementia: UK Biobank Cohort Study. 43, 140–150. https://doi.org/10.1007/s00127-007-0279-8.
BMJ Open 12 (2), e053936. Hay, D.F., Payne, A., Chadwick, A., 2004. Peer relations in childhood. J. Child Psychol.
Ennis, G.E., An, Y., Resnick, S.M., Ferrucci, L., O’Brien, R.J., Moffat, S.D., 2017. Long- Psychiatry 45, 84–108. https://doi.org/10.1046/j.0021-9630.2003.00308.x.
term cortisol measures predict Alzheimer disease risk. Neurology 88, 371–378. Heppner, F.L., Ransohoff, R.M., Becher, B., 2015. Immune attack: the role of
https://doi.org/10.1212/WNL.0000000000003537. inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372. https://doi.
Evans, I.E.M., Llewellyn, D.J., Matthews, F.E., Woods, R.T., Brayne, C., Clare, L., CFAS- org/10.1038/nrn3880.
Wales research team, 2019. Living alone and cognitive function in later life. Arch. Heser, K., Wagner, M., Wiese, B., Prokein, J., Ernst, A., König, H.-H., Brettschneider, C.,
Gerontol. Geriatr. 81, 222–233. https://doi.org/10.1016/j.archger.2018.12.014. Riedel-Heller, S.G., Luppa, M., Weyerer, S., Eifflaender-Gorfer, S., Bickel, H.,
Fernandez, C.G., Hamby, M.E., McReynolds, M.L., Ray, W.J., 2019. The Role of APOE4 in Mösch, E., Pentzek, M., Fuchs, A., Maier, W., Scherer, M., Eisele, M., 2014.
Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Associations between Dementia Outcomes and Depressive Symptoms, Leisure
Alzheimer’s Disease. Front. Aging Neurosci. 11, 14. https://doi.org/10.3389/ Activities, and Social Support. Dement. Geriatr. Cogn. Dis. Extra 4 (3), 481–493.
fnagi.2019.00014. Hinton, E.A., Li, D.C., Allen, A.G., Gourley, S.L., 2019. Social Isolation in Adolescence
Fischer, A., 2016. Environmental enrichment as a method to improve cognitive function. Disrupts Cortical Development and Goal-Dependent Decision-Making in Adulthood,
What can we learn from animal models? Neuroimage 131, 42–47. https://doi.org/ Despite Social Reintegration. eNeuro 6 (5). https://doi.org/10.1523/ENEURO.0318-
10.1016/j.neuroimage.2015.11.039. 19.2019.
Flicker, L., de la Torre, J.C., 2010. Modifiable lifestyle risk factors for Alzheimer’s
disease. J. Alzheimers. Dis. 20 (3), 803–811.
19
Hodes, G.E., Epperson, C.N., 2019. Sex Differences in Vulnerability and Resilience to Lander, S.S., Linder-Shacham, D., Gaisler-Salomon, I., 2017. Differential effects of social
Stress Across the Life Span. Biol. Psychiatry 86, 421–432. https://doi.org/10.1016/j. isolation in adolescent and adult mice on behavior and cortical gene expression.
biopsych.2019.04.028. Behav. Brain Res. 316, 245–254. https://doi.org/10.1016/j.bbr.2016.09.005.
Holmes, M.M., 2016. Social regulation of adult neurogenesis: A comparative approach. Lang, F.R., 2001. Regulation of social relationships in later adulthood. J. Gerontol. B
Front. Neuroendocrinol. 41, 59–70. https://doi.org/10.1016/j.yfrne.2016.02.001. Psychol. Sci. Soc. Sci. 56, P321–P326. https://doi.org/10.1093/geronb/56.6.p321.
Holt-Lunstad, J., 2021. Loneliness and social isolation as risk factors: The power of social Lara, E., Caballero, F.F., Rico-Uribe, L.A., Olaya, B., Haro, J.M., Ayuso-Mateos, J.L.,
connection in prevention. Am. J. Lifestyle Med. 15, 567–573. https://doi.org/ Miret, M., 2019. Are loneliness and social isolation associated with cognitive
10.1177/15598276211009454. decline? Int. J. Geriatr. Psychiatry 34, 1613–1622. https://doi.org/10.1002/
Holt-Lunstad, J., Smith, T.B., Baker, M., Harris, T., Stephenson, D., 2015. Loneliness and gps.5174.
social isolation as risk factors for mortality: a meta-analytic review. Perspect. Lavenda-Grosberg, D., Lalzar, M., Leser, N., Yaseen, A., Malik, A., Maroun, M., Barki-
Psychol. Sci. 10, 227–237. https://doi.org/10.1177/1745691614568352. Harrington, L., Wagner, S., 2022. Acute social isolation and regrouping cause short-
Holvast, F., Burger, H., de Waal, M.M.W., van Marwijk, H.W.J., Comijs, H.C., Verhaak, P. and long-term molecular changes in the rat medial amygdala. Mol. Psychiatry 27,
F.M., 2015. Loneliness is associated with poor prognosis in late-life depression: 886–895. https://doi.org/10.1038/s41380-021-01342-4.
Longitudinal analysis of the Netherlands study of depression in older persons. Lee, C.R., Chen, A., Tye, K.M., 2021. The neural circuitry of social homeostasis:
J. Affect. Disord. 185, 1–7. https://doi.org/10.1016/j.jad.2015.06.036. Consequences of acute versus chronic social isolation. Cell 184, 2794–2795. https://
Holwerda, T.J., Beekman, A.T.F., Deeg, D.J.H., Stek, M.L., van Tilburg, T.G., Visser, P.J., doi.org/10.1016/j.cell.2021.04.044.
Schmand, B., Jonker, C., Schoevers, R.A., 2012. Increased risk of mortality Lee, J.-S., Kang, J.-Y., Son, C.-G., 2020. A Comparison of Isolation Stress and
associated with social isolation in older men: only when feeling lonely? Results from Unpredictable Chronic Mild Stress for the Establishment of Mouse Models of
the Amsterdam Study of the Elderly (AMSTEL). Psychol. Med. 42, 843–853. https:// Depressive Disorder. Front. Behav. Neurosci. 14, 616389 https://doi.org/10.3389/
doi.org/10.1017/S0033291711001772. fnbeh.2020.616389.
Holwerda, T.J., Deeg, D.J.H., Beekman, A.T.F., van Tilburg, T.G., Stek, M.L., Jonker, C., Leigh-Hunt, N., Bagguley, D., Bash, K., Turner, V., Turnbull, S., Valtorta, N., Caan, W.,
Schoevers, R.A., 2014. Feelings of loneliness, but not social isolation, predict 2017. An overview of systematic reviews on the public health consequences of social
dementia onset: results from the Amsterdam Study of the Elderly (AMSTEL). isolation and loneliness. Public Health 152, 157–171. https://doi.org/10.1016/j.
J. Neurol. Neurosurg. Psychiatry 85, 135–142. https://doi.org/10.1136/jnnp-2012- puhe.2017.07.035.
302755. Leitzmann, M.F., Park, Y., Blair, A., Ballard-Barbash, R., Mouw, T., Hollenbeck, A.R.,
Hooper, C., Killick, R., Lovestone, S., 2008. The GSK3 hypothesis of Alzheimer’s disease. Schatzkin, A., 2007. Physical activity recommendations and decreased risk of
J. Neurochem. 104, 1433–1439. https://doi.org/10.1111/j.1471-4159.2007.05194. mortality. Arch. Intern. Med. 167, 2453–2460. https://doi.org/10.1001/
x. archinte.167.22.2453.
Hsiao, Y.-H., Chen, P.S., Chen, S.-H., Gean, P.-W., 2011. The involvement of Cdk5 Li, X.-L., Hu, N., Tan, M.-S., Yu, J.-T., Tan, L., 2014. Behavioral and Psychological
activator p35 in social isolation-triggered onset of early Alzheimer’s disease-related Symptoms in Alzheimer’s Disease. Biomed Res. Int. 2014, 1–9.
cognitive deficit in the transgenic mice. Neuropsychopharmacology 36, 1848–1858. Liang, F., Yang, S., Zhang, Y., Hao, T., 2019. Social housing promotes cognitive function
https://doi.org/10.1038/npp.2011.69. through enhancing synaptic plasticity in APP/PS1 mice. Behav. Brain Res. 368,
Hsiao, Y.-H., Kuo, J.-R., Chen, S.-H., Gean, P.-W., 2012. Amelioration of social isolation- 111910 https://doi.org/10.1016/j.bbr.2019.111910.
triggered onset of early Alzheimer’s disease-related cognitive deficit by N- Lieberwirth, C., Wang, Z., 2012. The social environment and neurogenesis in the adult
acetylcysteine in a transgenic mouse model. Neurobiol. Dis. 45, 1111–1120. https:// Mammalian brain. Front. Hum. Neurosci. 6, 118. https://doi.org/10.3389/
doi.org/10.1016/j.nbd.2011.12.031. fnhum.2012.00118.
Hsiao, Y.-H., Hung, H.-C., Chen, S.-H., Gean, P.-W., 2014. Social interaction rescues Liu, Y., Lv, L., Wang, L., Zhong, Y., 2018. Social Isolation Induces Rac1-Dependent
memory deficit in an animal model of Alzheimer’s disease by increasing BDNF- Forgetting of Social Memory. Cell Rep. 25, 288–295.e3. https://doi.org/10.1016/j.
dependent hippocampal neurogenesis. J. Neurosci. 34, 16207–16219. https://doi. celrep.2018.09.033.
org/10.1523/JNEUROSCI.0747-14.2014. Lobo, A., Saz, P., Marcos, G., Día, J.-L., De-la-Cámara, C., Ventura, T., Montañés, J.A.,
Huang, H.-J., Liang, K.-C., Ke, H.-C., Chang, Y.-Y., Hsieh-Li, H.M., 2011. Long-term social Lobo-Escolar, A., Aznar, S., 2005. The ZARADEMP Project on the incidence,
isolation exacerbates the impairment of spatial working memory in APP/PS1 prevalence and risk factors of dementia (and depression) in the elderly community:
transgenic mice. Brain Res. 1371, 150–160. https://doi.org/10.1016/j. II. Methods and first results. Eur. J. Psychiat. 19, 40–54.
brainres.2010.11.043. Lobo, A., LóPez-Antón, R., De-La-CÁmara, C., Quintanilla, M.Á., Campayo, A., Saz, P.,
Huang, H., Wang, L., Cao, M., Marshall, C., Gao, J., Xiao, N., Hu, G., Xiao, M., 2015. Workgroup, Z., 2008. Non-cognitive psychopathological symptoms associated with
Isolation Housing Exacerbates Alzheimer’s Disease-Like Pathophysiology in Aged incident mild cognitive impairment and dementia, alzheimer’s type. Neurotox. Res.
APP/PS1 Mice. Int. J. Neuropsychopharmacol. 18 (7), pyu116. 14, 263–272. https://doi.org/10.1007/BF03033815.
Joshi, Y.B., Giannopoulos, P.F., Chu, J., Sperow, M., Kirby, L.G., Abood, M.E., Praticò, D., Loucks, E.B., Berkman, L.F., Gruenewald, T.L., Seeman, T.E., 2006a. Relation of social
2014. Absence of ALOX5 gene prevents stress-induced memory deficits, synaptic integration to inflammatory marker concentrations in men and women 70 to 79
dysfunction and tauopathy in a mouse model of Alzheimer’s disease. Hum. Mol. years. Am. J. Cardiol. 97, 1010–1016. https://doi.org/10.1016/j.
Genet. 23, 6894–6902. https://doi.org/10.1093/hmg/ddu412. amjcard.2005.10.043.
Kahan, B.C., Jairath, V., Doré, C.J., Morris, T.P., 2014. The risks and rewards of covariate Loucks, E.B., Sullivan, L.M., D’Agostino Sr, R.B., Larson, M.G., Berkman, L.F.,
adjustment in randomized trials: an assessment of 12 outcomes from 8 studies. Trials Benjamin, E.J., 2006b. Social networks and inflammatory markers in the
15, 139. https://doi.org/10.1186/1745-6215-15-139. Framingham Heart Study. J. Biosoc. Sci. 38, 835–842. https://doi.org/10.1017/
Kang, J.-E., Cirrito, J.R., Dong, H., Csernansky, J.G., Holtzman, D.M., 2007. Acute stress S0021932005001203.
increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal Lu, L., Bao, G., Chen, H., Xia, P., Fan, X., Zhang, J., Pei, G., Ma, L., 2003. Modification of
activity. Proc. Natl. Acad. Sci. 104, 10673–10678. https://doi.org/10.1073/ hippocampal neurogenesis and neuroplasticity by social environments. Exp. Neurol.
pnas.0700148104. 183, 600–609. https://doi.org/10.1016/s0014-4886(03)00248-6.
Karp, A., Paillard-Borg, S., Wang, H.-X., Silverstein, M., Winblad, B., Fratiglioni, L., 2006. Luchetti, M., Terracciano, A., Aschwanden, D., Lee, J.H., Stephan, Y., Sutin, A.R., 2020.
Mental, physical and social components in leisure activities equally contribute to Loneliness is associated with risk of cognitive impairment in the Survey of Health,
decrease dementia risk. Dement. Geriatr. Cogn. Disord. 21, 65–73. https://doi.org/ Ageing and Retirement in Europe. Int. J. Geriatr. Psychiatry 35, 794–801. https://
10.1159/000089919. doi.org/10.1002/gps.5304.
Khan, U.A., Liu, L., Provenzano, F.A., Berman, D.E., Profaci, C.P., Sloan, R., Mayeux, R., Lukkes, J.L., Mokin, M.V., Scholl, J.L., Forster, G.L., 2009a. Adult rats exposed to early-
Duff, K.E., Small, S.A., 2014. Molecular drivers and cortical spread of lateral life social isolation exhibit increased anxiety and conditioned fear behavior, and
entorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nat. Neurosci. 17, altered hormonal stress responses. Horm. Behav. 55, 248–256. https://doi.org/
304–311. https://doi.org/10.1038/nn.3606. 10.1016/j.yhbeh.2008.10.014.
Khondoker, M., Rafnsson, S.B., Morris, S., Orrell, M., Steptoe, A., 2017. Positive and Lukkes, J.L., Watt, M.J., Lowry, C.A., Forster, G.L., 2009b. Consequences of post-weaning
Negative Experiences of Social Support and Risk of Dementia in Later Life: An social isolation on anxiety behavior and related neural circuits in rodents. Front.
Investigation Using the English Longitudinal Study of Ageing. J. Alzheimers. Dis. 58, Behav. Neurosci. 3, 18. https://doi.org/10.3389/neuro.08.018.2009.
99–108. https://doi.org/10.3233/JAD-161160. Mandelkow, E.M., Drewes, G., Biernat, J., Gustke, N., Van Lint, J., Vandenheede, J.R.,
Kiecolt-Glaser, J.K., Gouin, J.-P., Hantsoo, L., 2010. Close relationships, inflammation, Mandelkow, E., 1992. Glycogen synthase kinase-3 and the Alzheimer-like state of
and health. Neurosci. Biobehav. Rev. 35, 33–38. https://doi.org/10.1016/j. microtubule-associated protein tau. FEBS Lett. 314, 315–321. https://doi.org/
neubiorev.2009.09.003. 10.1016/0014-5793(92)81496-9.
Kolanowski, A., Buettner, L., 2008. Prescribing activities that engage passive residents. Marioni, R.E., Proust-Lima, C., Amieva, H., Brayne, C., Matthews, F.E., Dartigues, J.-F.,
An innovative method. J. Gerontol. Nurs. 34, 13–18. https://doi.org/10.3928/ Jacqmin-Gadda, H., 2015. Social activity, cognitive decline and dementia risk: a 20-
00989134-20080101-08. year prospective cohort study. BMC Public Health 15, 1089. https://doi.org/
Kondrakiewicz, K., Kostecki, M., Szadzińska, W., Knapska, E., 2019. Ecological validity 10.1186/s12889-015-2426-6.
of social interaction tests in rats and mice. Genes Brain Behav. 18 (1), e12525. Matsumoto, K., Fujiwara, H., Araki, R., Yabe, T., 2019. Post-weaning social isolation of
Kuiper, J.S., Smidt, N., Zuidema, S.U., Comijs, H.C., Oude Voshaar, R.C., Zuidersma, M., mice: A putative animal model of developmental disorders. J. Pharmacol. Sci. 141,
2020. A longitudinal study of the impact of social network size and loneliness on 111–118. https://doi.org/10.1016/j.jphs.2019.10.002.
cognitive performance in depressed older adults. Aging Ment. Health 24, 889–897. McPherson, M., Smith-Lovin, L., Brashears, M.E., 2006. Social Isolation in America:
https://doi.org/10.1080/13607863.2019.1571012. Changes in Core Discussion Networks over Two Decades. Am. Sociol. Rev. 71,
Kujala, U.M., Kaprio, J., Sarna, S., Koskenvuo, M., 1998. Relationship of leisure-time 353–375. https://doi.org/10.1177/000312240607100301.
physical activity and mortality: the Finnish twin cohort. JAMA 279, 440–444. Medendorp, W.E., Petersen, E.D., Pal, A., Wagner, L.-M., Myers, A.R.,
https://doi.org/10.1001/jama.279.6.440. Hochgeschwender, U., Jenrow, K.A., 2018. Altered Behavior in Mice Socially
Isolated During Adolescence Corresponds With Immature Dendritic Spine
20
Morphology and Impaired Plasticity in the Prefrontal Cortex. Front. Behav. Neurosci. Pugh, E., De Vito, A., Divers, R., Robinson, A., Weitzner, D.S., Calamia, M., 2021. Social
https://doi.org/10.3389/fnbeh.2018.00087. factors that predict cognitive decline in older African American adults. Int. J. Geriatr.
Mielke, M.M., 2018. Sex and gender differences in Alzheimer’s disease dementia. Psychiatry 36, 403–410. https://doi.org/10.1002/gps.5435.
Psychiatr. Times 35, 14–17. Rafnsson, S.B., Orrell, M., d’Orsi, E., Hogervorst, E., Steptoe, A., Carr, D., 2020.
Miller, G.E., Chen, E., Zhou, E.S., 2007. If it goes up, must it come down? Chronic stress Loneliness, Social Integration, and Incident Dementia Over 6 Years: Prospective
and the hypothalamic-pituitary-adrenocortical axis in humans. Psychol. Bull. 133, Findings From the English Longitudinal Study of Ageing. J. Gerontol. B Psychol. Sci.
25–45. https://doi.org/10.1037/0033-2909.133.1.25. Soc. Sci. 75 (1), 114–124.
Mirra, S.S., Hart, M.N., Terry, R.D., 1993. Making the diagnosis of Alzheimer’s disease. A Rawtaer, Iris, Gao, Qi, Nyunt, Ma Shwe Zin, Feng, Lei, Chong, Mei Sian, Lim, Wee
primer for practicing pathologists. Arch. Pathol. Lab. Med. 117, 132–144. Shiong, Lee, Tih-Shih, Yap, Philip, Yap, Keng Bee, Ng, Tze Pin, 2017. Psychosocial
Montoliu, T., Hidalgo, V., Salvador, A., 2019. The relationship between loneliness and Risk and Protective Factors and Incident Mild Cognitive Impairment and Dementia
cognition in healthy older men and women: The role of cortisol. in Community Dwelling Elderly: Findings from the Singapore Longitudinal Ageing
Psychoneuroendocrinology 107, 270–279. https://doi.org/10.1016/j. Study. J. Alzheimers Dis. 57 (2), 603–611. https://doi.org/10.3233/JAD-160862.
psyneuen.2019.05.024. Regenass, W., Möller, M., Harvey, B.H., 2018. Studies into the anxiolytic actions of
Neel, R., Kenrick, D.T., White, A.E., Neuberg, S.L., 2016. Individual differences in agomelatine in social isolation reared rats: Role of corticosterone and sex.
fundamental social motives. J. Pers. Soc. Psychol. 110, 887–907. https://doi.org/ J. Psychopharmacol. 32, 134–145. https://doi.org/10.1177/0269881117735769.
10.1037/pspp0000068. Ren, Q.-G., Gong, W.-G., Wang, Y.-J., Zhou, Q.-D., Zhang, Z.-J., 2015. Citalopram
Newcombe, E.A., Camats-Perna, J., Silva, M.L., Valmas, N., Huat, T.J., Medeiros, R., attenuates tau hyperphosphorylation and spatial memory deficit induced by social
2018. Inflammation: the link between comorbidities, genetics, and Alzheimer’s isolation rearing in middle-aged rats. J. Mol. Neurosci. 56, 145–153. https://doi.org/
disease. J. Neuroinflammation 15, 276. https://doi.org/10.1186/s12974-018-1313- 10.1007/s12031-014-0475-4.
3. Rivera, D.S., Lindsay, C.B., Oliva, C.A., Codocedo, J.F., Bozinovic, F., Inestrosa, N.C.,
Niwa, M., Matsumoto, Y., Mouri, A., Ozaki, N., Nabeshima, T., 2011. Vulnerability in 2020. Effects of long-lasting social isolation and re-socialization on cognitive
early life to changes in the rearing environment plays a crucial role in the performance and brain activity: a longitudinal study in Octodon degus. Sci. Rep. 10,
aetiopathology of psychiatric disorders. Int. J. Neuropsychopharmacol. 14, 459–477. 18315. https://doi.org/10.1038/s41598-020-75026-4.
https://doi.org/10.1017/S1461145710001239. Rodriguez, F.S., Pabst, A., Luck, T., König, H.-H., Angermeyer, M.C., Witte, A.V.,
O’Luanaigh, C., O’Connell, H., Chin, A.-V., Hamilton, F., Coen, R., Walsh, C., Walsh, J.B., Villringer, A., Riedel-Heller, S.G., 2018. Social Network Types in Old Age and
Caokley, D., Cunningham, C., Lawlor, B.A., 2012. Loneliness and cognition in older Incident Dementia. J. Geriatr. Psychiatry Neurol. 31, 163–170. https://doi.org/
people: the Dublin Healthy Ageing study. Aging Ment. Health 16, 347–352. https:// 10.1177/0891988718781041.
doi.org/10.1080/13607863.2011.628977. Ruland, C., Berlandi, J., Eikmeier, K., Weinert, T., Lin, F.J., Ambree, O., Seggewiss, J.,
Olajide, O.J., Suvanto, M.E., Chapman, C.A., 2021. Molecular mechanisms of Paulus, W., Jeibmann, A., 2018. Decreased cerebral Irp-1B limits impact of social
neurodegeneration in the entorhinal cortex that underlie its selective vulnerability isolation in wild type and Alzheimer’s disease modeled in Drosophila melanogaster.
during the pathogenesis of Alzheimer’s disease. Biol. Open 10. https://doi.org/ Genes Brain Behav. 17 (5), e12451.
10.1242/bio.056796. Salinas, J., Beiser, A., Himali, J.J., Satizabal, C.L., Aparicio, H.J., Weinstein, G.,
Ouanes, S., Popp, J., 2019. High cortisol and the risk of dementia and Alzheimer’s Mateen, F.J., Berkman, L.F., Rosand, J., Seshadri, S., 2017. Associations between
disease: A review of the literature. Front. Aging Neurosci. 11, 43. https://doi.org/ social relationship measures, serum brain-derived neurotrophic factor, and risk of
10.3389/fnagi.2019.00043. stroke and dementia. Alzheimers. Dement. 3, 229–237. https://doi.org/10.1016/j.
Paillard-Borg, S., Fratiglioni, L., Winblad, B., Wang, H.-X., 2009. Leisure activities in late trci.2017.03.001.
life in relation to dementia risk: principal component analysis. Dement. Geriatr. Salinas, J., Beiser, A.S., Samra, J.K., O’Donnell, A., DeCarli, C.S., Gonzales, M.M.,
Cogn. Disord. 28, 136–144. https://doi.org/10.1159/000235576. Aparicio, H.J., Seshadri, S., 2022. Association of Loneliness With 10-Year Dementia
Park, J.-S., Kam, T.-I., Lee, S., Park, H., Oh, Y., Kwon, S.-H., Song, J.-J., Kim, D., Kim, H., Risk and Early Markers of Vulnerability for Neurocognitive Decline. Neurology 98,
Jhaldiyal, A., Na, D.H., Lee, K.C., Park, E.J., Pomper, M.G., Pletnikova, O., e1337–e1348. https://doi.org/10.1212/WNL.0000000000200039.
Troncoso, J.C., Ko, H.S., Dawson, V.L., Dawson, T.M., Lee, S., 2021b. Blocking Sallet, J., Mars, R.B., Noonan, M.P., Andersson, J.L., O’Reilly, J.X., Jbabdi, S., Croxson, P.
microglial activation of reactive astrocytes is neuroprotective in models of L., Jenkinson, M., Miller, K.L., Rushworth, M.F.S., 2011. Social network size affects
Alzheimer’s disease. Acta Neuropathol. Commun. 9, 78. https://doi.org/10.1186/ neural circuits in macaques. Science 334, 697–700. https://doi.org/10.1126/
s40478-021-01180-z. science.1210027.
Park, G., Ryu, C., Kim, S., Jeong, S.J., Koo, J.W., Lee, Y.-S., Kim, S.J., 2021a. Social Santini, Z.I., Koyanagi, A., Tyrovolas, S., Mason, C., Haro, J.M., 2015. The association
isolation impairs the prefrontal-nucleus accumbens circuit subserving social between social relationships and depression: a systematic review. J. Affect. Disord.
recognition in mice. Cell Rep. 35 (6), 109104. 175, 53–65. https://doi.org/10.1016/j.jad.2014.12.049.
Penninkilampi, R., Casey, A.-N., Singh, M.F., Brodaty, H., 2018. The Association between Sapolsky, R.M., 1999. Glucocorticoids, stress, and their adverse neurological effects:
Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and relevance to aging. Exp. Gerontol. 34, 721–732. https://doi.org/10.1016/s0531-
Meta-Analysis. J. Alzheimers. Dis. 66, 1619–1633. https://doi.org/10.3233/JAD- 5565(99)00047-9.
180439. Sargin, D., Oliver, D.K., Lambe, E.K., 2016. Chronic social isolation reduces 5-HT
Pereda-Pérez, I., Popović, N., Otalora, B.B., Popović, M., Madrid, J.A., Rol, M.A., neuronal activity via upregulated SK3 calcium-activated potassium channels. Elife 5.
Venero, C., 2013. Long-term social isolation in the adulthood results in CA1 https://doi.org/10.7554/eLife.21416.
shrinkage and cognitive impairment. Neurobiol. Learn. Mem. 106, 31–39. https:// Sargin, D., Chottekalapanda, R.U., Perit, K.E., Yao, V., Chu, D., Sparks, D.W., Kalik, S.,
doi.org/10.1016/j.nlm.2013.07.004. Power, S.K., Troyanskaya, O.G., Schmidt, E.F., Greengard, P., Lambe, E.K., 2019.
Perissinotto, C.M., Covinsky, K.E., 2014. Living alone, socially isolated or lonely–what Mapping the physiological and molecular markers of stress and SSRI antidepressant
are we measuring? J. Gen Intern. Med. 29 (11), 1429–1431. treatment in S100a10 corticostriatal neurons. Mol. Psychiatry. 25 (5), 1112–1129.
Peterman, J.L., White, J.D., Calcagno, A., Hagen, C., Quiring, M., Paulhus, K., Gurney, T., Shahar-Gold, H., Gur, R., Wagner, S., Burne, T., 2013. Rapid and reversible impairments
Eimerbrink, M.J., Curtis, M., Boehm, G.W., Chumley, M.J., 2020. Prolonged isolation of short- and long-term social recognition memory are caused by acute isolation of
stress accelerates the onset of Alzheimer’s disease-related pathology in 5xFAD mice adult rats via distinct mechanisms. PLoS One 8 (5), e65085.
despite running wheels and environmental enrichment. Behav. Brain Res. 379, Shankar, A., McMunn, A., Banks, J., Steptoe, A., 2011. Loneliness, social isolation, and
112366. behavioral and biological health indicators in older adults. Health Psychol. 30,
Petersen, R.C., 2004. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 377–385. https://doi.org/10.1037/a0022826.
256, 183–194. https://doi.org/10.1111/j.1365-2796.2004.01388.x. Shankar, A., Hamer, M., McMunn, A., Steptoe, A., 2013. Social isolation and loneliness:
Petersen, R.C., Jack Jr, C.R., 2009. Imaging and biomarkers in early Alzheimer’s disease relationships with cognitive function during 4 years of follow-up in the English
and mild cognitive impairment. Clin. Pharmacol. Ther. 86, 438–441. https://doi. Longitudinal Study of Ageing. Psychosom. Med. 75, 161–170. https://doi.org/
org/10.1038/clpt.2009.166. 10.1097/PSY.0b013e31827f09cd.
Pietropaolo, S., Branchi, I., Cirulli, F., Chiarotti, F., Aloe, L., Alleva, E., 2004. Long-term Shen, C., Rolls, E.T., Cheng, W., Kang, J., Dong, G., Xie, C., Zhao, X.-M., Sahakian, B.J.,
effects of the periadolescent environment on exploratory activity and aggressive Feng, J., 2022. Associations of Social Isolation and Loneliness With Later Dementia.
behaviour in mice: social versus physical enrichment. Physiol. Behav. 81, 443–453. Neurology 99 (2), e164–e175.
https://doi.org/10.1016/j.physbeh.2004.02.022. Smith, L., Bloska, J., Jacob, L., Barnett, Y., Butler, L., Trott, M., Odell-Miller, H.,
Pietropaolo, S., Sun, Y., Li, R., Brana, C., Feldon, J., Yee, B.K., 2009. Limited impact of Veronese, N., Kostev, K., Bettac, E.L., Godier-McBard, L., Koyanagi, A., 2021. Is
social isolation on Alzheimer-like symptoms in a triple transgenic mouse model. loneliness associated with mild cognitive impairment in low- and middle-income
Behav. Neurosci. 123, 181–195. https://doi.org/10.1037/a0013607. countries? Int. J. Geriatr. Psychiatry 36, 1345–1353. https://doi.org/10.1002/
Pillai, J.A., Verghese, J., 2009. Social networks and their role in preventing dementia. gps.5524.
Indian J. Psychiatry 51 (Suppl 1), S22–S28. Smith, B.L., Lyons, C.E., Correa, F.G., Benoit, S.C., Myers, B., Solomon, M.B., Herman, J.
Pisu, M.G., Garau, A., Boero, G., Biggio, F., Pibiri, V., Dore, R., Locci, V., Paci, E., P., 2017. Behavioral and physiological consequences of enrichment loss in rats.
Porcu, P., Serra, M., 2016. Sex differences in the outcome of juvenile social isolation Psychoneuroendocrinology 77, 37–46. https://doi.org/10.1016/j.
on HPA axis function in rats. Neuroscience 320, 172–182. https://doi.org/10.1016/ psyneuen.2016.11.040.
j.neuroscience.2016.02.009. Sommerlad, A., Sabia, S., Singh-Manoux, A., Lewis, G., Livingston, G., Yasar, S., 2019.
Poey, J.L., Burr, J.A., Roberts, J.S., 2017. Social Connectedness, Perceived Isolation, and Association of social contact with dementia and cognition: 28-year follow-up of the
Dementia: Does the Social Environment Moderate the Relationship Between Genetic Whitehall II cohort study. PLoS Med. 16 (8), e1002862.
Risk and Cognitive Well-Being? Gerontologist 57, 1031–1040. https://doi.org/ Sörman, D.E., Rönnlund, M., Sundström, A., Adolfsson, R., Nilsson, L.-G., 2015. Social
10.1093/geront/gnw154. relationships and risk of dementia: a population-based study. Int. Psychogeriatr. 27,
1391–1399. https://doi.org/10.1017/S1041610215000319.
21
Steptoe, A., Shankar, A., Demakakos, P., Wardle, J., 2013. Social isolation, loneliness, review and meta-analysis of longitudinal observational studies. Heart 102,
and all-cause mortality in older men and women. Proc. Natl. Acad. Sci. U. S. A. 110, 1009–1016. https://doi.org/10.1136/heartjnl-2015-308790.
5797–5801. https://doi.org/10.1073/pnas.1219686110. Verghese, J., Lipton, R.B., Katz, M.J., Hall, C.B., Derby, C.A., Kuslansky, G., Ambrose, A.
Stozická, Z., Zilka, N., Novák, M., 2007. Risk and protective factors for sporadic F., Sliwinski, M., Buschke, H., 2003. Leisure activities and the risk of dementia in the
Alzheimer’s disease. Acta Virol. 51, 205–222. elderly. N. Engl. J. Med. 348, 2508–2516. https://doi.org/10.1056/NEJMoa022252.
Su, S., Shi, L., Zheng, Y., Sun, Y., Huang, X., Zhang, A., Que, J., Sun, X., Shi, J., Bao, Y., Walker, D.M., Cunningham, A.M., Gregory, J.K., Nestler, E.J., 2019. Long-term
Deng, J., Lu, L., 2022. Leisure Activities and the Risk of Dementia. Neurology 99, behavioral effects of post-weaning social isolation in males and females. Front.
e1651–e1663. https://doi.org/10.1212/WNL.0000000000200929. Behav. Neurosci. 13, 66. https://doi.org/10.3389/fnbeh.2019.00066.
Sullens, D.G., Gilley, K., Jensen, K., Vichaya, E., Dolan, S.L., Sekeres, M.J., Wang, H.-X., Karp, A., Winblad, B., Fratiglioni, L., 2002. Late-life engagement in social
Kavushansky, A., 2021. Social isolation induces hyperactivity and exploration in and leisure activities is associated with a decreased risk of dementia: a longitudinal
aged female mice. PLoS One 16 (2), e0245355. study from the Kungsholmen project. Am. J. Epidemiol. 155, 1081–1087. https://
Sundström, A., Westerlund, O., Mousavi-Nasab, H., Adolfsson, R., Nilsson, L.-G., 2014. doi.org/10.1093/aje/155.12.1081.
The relationship between marital and parental status and the risk of dementia. Int. Wang, H., Lee, C., Hunter, S., Fleming, J., Brayne, C., 2020. Longitudinal analysis of the
Psychogeriatr. 26, 749–757. https://doi.org/10.1017/S1041610213002652. impact of loneliness on cognitive function over a 20-year follow-up. Aging Ment.
Sundström, A., Adolfsson, A.N., Nordin, M., Adolfsson, R., Anderson, N., 2020. Health 24 (11), 1815–1821.
Loneliness Increases the Risk of All-Cause Dementia and Alzheimer’s Disease. Wilson, R.S., Krueger, K.R., Arnold, S.E., Schneider, J.A., Kelly, J.F., Barnes, L.L.,
J. Gerontol. B Psychol. Sci. Soc. Sci. 75 (5), 919–926. Tang, Y., Bennett, D.A., 2007. Loneliness and risk of Alzheimer disease. Arch. Gen.
Sutcliffe, A., Dunbar, R., Binder, J., Arrow, H., 2012. Relationships and the social brain: Psychiatry 64, 234–240. https://doi.org/10.1001/archpsyc.64.2.234.
integrating psychological and evolutionary perspectives. Br. J. Psychol. 103, Yamamuro, K., Bicks, L.K., Leventhal, M.B., Kato, D., Im, S., Flanigan, M.E., Garkun, Y.,
149–168. https://doi.org/10.1111/j.2044-8295.2011.02061.x. Norman, K.J., Caro, K., Sadahiro, M., Kullander, K., Akbarian, S., Russo, S.J.,
Sutin, A.R., Stephan, Y., Luchetti, M., Terracciano, A., Martire, L., 2020. Loneliness and Morishita, H., 2020. A prefrontal–paraventricular thalamus circuit requires juvenile
Risk of Dementia. J. Gerontol. B Psychol. Sci. Soc. Sci. 75 (7), 1414–1422. social experience to regulate adult sociability in mice. Nat. Neurosci. 23, 1240–1252.
Tamano, H., Ide, K., Adlard, P.A., Bush, A.I., Takeda, A., 2016. Involvement of https://doi.org/10.1038/s41593-020-0695-6.
hippocampal excitability in amyloid β-induced behavioral and psychological Yin, J., Lassale, C., Steptoe, A., Cadar, D., 2019. Exploring the bidirectional associations
symptoms of dementia. J. Toxicol. Sci. 41, 449–457. https://doi.org/10.2131/ between loneliness and cognitive functioning over 10 years: the English longitudinal
jts.41.449. study of ageing. Int. J. Epidemiol. 48, 1937–1948. https://doi.org/10.1093/ije/
Tariot, P.N., Mack, J.L., Patterson, M.B., Edland, S.D., Weiner, M.F., Fillenbaum, G., dyz085.
Blazina, L., Teri, L., Rubin, E., Mortimer, J.A., 1995. The Behavior Rating Scale for Yu, B., Steptoe, A., Chen, Y., Jia, X., 2021. Social isolation, rather than loneliness, is
Dementia of the Consortium to Establish a Registry for Alzheimer’s Disease. The associated with cognitive decline in older adults: the China Health and Retirement
Behavioral Pathology Committee of the Consortium to Establish a Registry for Longitudinal Study. Psychol. Med. 51, 2414–2421. https://doi.org/10.1017/
Alzheimer’s Disease. Am. J. Psychiatry 152, 1349–1357. https://doi.org/10.1176/ S0033291720001014.
ajp.152.9.1349. Zebhauser, A., Hofmann-Xu, L., Baumert, J., Häfner, S., Lacruz, M.E., Emeny, R.T.,
Taylor, H.O., Taylor, R.J., Nguyen, A.W., Chatters, L., 2018. Social isolation, depression, Döring, A., Grill, E., Huber, D., Peters, A., Ladwig, K.H., 2014. How much does it
and psychological distress among older adults. J. Aging Health 30, 229–246. https:// hurt to be lonely? Mental and physical differences between older men and women in
doi.org/10.1177/0898264316673511. the KORA-Age Study. Int. J. Geriatr. Psychiatry 29, 245–252. https://doi.org/
Teo, A.R., Lerrigo, R., Rogers, M.A.M., 2013. The role of social isolation in social anxiety 10.1002/gps.3998.
disorder: a systematic review and meta-analysis. J. Anxiety Disord. 27, 353–364. Zelikowsky, M., Hui, M., Karigo, T., Choe, A., Yang, B., Blanco, M.R., Beadle, K.,
https://doi.org/10.1016/j.janxdis.2013.03.010. Gradinaru, V., Deverman, B.E., Anderson, D.J., 2018. The Neuropeptide Tac2
Touma, C., Ambrée, O., Görtz, N., Keyvani, K., Lewejohann, L., Palme, R., Paulus, W., Controls a Distributed Brain State Induced by Chronic Social Isolation Stress. Cell
Schwarze-Eicker, K., Sachser, N., 2004. Age- and sex-dependent development of 173, 1265–1279.e19. https://doi.org/10.1016/j.cell.2018.03.037.
adrenocortical hyperactivity in a transgenic mouse model of Alzheimer’s disease. Zhang, J., Liu, D., Fu, P., Liu, Z.-Q., Lai, C., Yang, C.-Q., Chen, K., Bao, W.-D., Hu, F.,
Neurobiol. Aging 25, 893–904. https://doi.org/10.1016/j. Du, H.-Y., Yang, W., Wang, J., Man, H.-Y., Lu, Y., Zhu, L.-Q., 2022a. Social isolation
neurobiolaging.2003.09.004. reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis
Tseng, H.C., Zhou, Y., Shen, Y., Tsai, L.H., 2002. A survey of Cdk5 activator p35 and p25 in basolateral amygdala. Mol. Psychiatry. 27 (10), 4050–4063.
levels in Alzheimer’s disease brains. FEBS Lett. 523, 58–62. https://doi.org/ Zhang, Y., Tatewaki, Y., Liu, Y., Tomita, N., Nagasaka, T., Muranaka, M., Yamamoto, S.,
10.1016/s0014-5793(02)02934-4. Takano, Y., Nakase, T., Mutoh, T., Taki, Y., 2022b. Perceived social isolation is
Uvnäs Moberg, K., Petersson, M., 2006. Antistress, Well-Being, Empathy and Social correlated with brain structure and cognitive trajectory in Alzheimer’s disease.
Support. Stress in health and disease. https://doi.org/10.1002/ Geroscience 44, 1563–1574. https://doi.org/10.1007/s11357-022-00584-6.
3527609156#page=245. Zhong, B.-L., Chen, S.-L., Tu, X., Conwell, Y., 2017. Loneliness and Cognitive Function in
Uys, M., Shahid, M., Sallinen, J., Dreyer, W., Cockeran, M., Harvey, B.H., 2016. The α2C- Older Adults: Findings From the Chinese Longitudinal Healthy Longevity Survey.
adrenoceptor antagonist, ORM-10921, has antipsychotic-like effects in social J. Gerontol. B Psychol. Sci. Soc. Sci. 72, 120–128. https://doi.org/10.1093/geronb/
isolation reared rats and bolsters the response to haloperidol. Progr. Neuro- gbw037.
Psychopharmacol. Biol. Psychiatry 71, 108–116. https://doi.org/10.1016/j. Zhou, Z., Wang, P., Fang, Y., 2018. Loneliness and the risk of dementia among older
pnpbp.2016.07.002. Chinese adults: gender differences. Aging Ment. Health 22, 519–525. https://doi.
Valtorta, N.K., Kanaan, M., Gilbody, S., Ronzi, S., Hanratty, B., 2016. Loneliness and org/10.1080/13607863.2016.1277976.
social isolation as risk factors for coronary heart disease and stroke: systematic
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Frontiers in Neuroendocrinology 69 (2023) 101061

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The impact of loneliness and social isolation on the development of

1. Introduction subjective perception of an unfulfilled level of social contact and feelings

(Increased CRF after acute restraint but not in mice

Immunoblotting and Immunoprecipitation:

Calpain activity assay kit:

Agarose gel electrophoresis:

Total: 1203 NA Incidence rate of dementia NA Fratiglioni et al.

Total: 1477 NA F: higher incidence of all cause NA Sundström et al.

between loneliness and the AD-related pathological changes (d’Oleire Acknowledgements

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