Genes Associated With Alzheimer's Disease: An Overview and Current Status

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Genes associated with Alzheimer’s disease:

an overview and current status
This article was published in the following Dove Press journal:
Clinical Interventions in Aging
17 May 2016
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Mohan Giri Abstract: Alzheimer’s disease (AD) is a progressive, neurodegenerative disease and the
Man Zhang most common form of dementia in elderly people. It is an emerging public health problem
Yang Lü that poses a huge societal burden. Linkage analysis was the first milestone in unraveling the
mutations in APP, PSEN1, and PSEN2 that cause early-onset AD, followed by the discovery of
Department of Geriatrics, The First
Affiliated Hospital of Chongqing apolipoprotein E-ε4 allele as the only one genetic risk factor for late-onset AD. Genome-wide
Medical University, Yuzhong District, association studies have revolutionized genetic research and have identified over 20 genetic
Chongqing, People’s Republic of China
loci associated with late-onset AD. Recently, next-generation sequencing technologies have
enabled the identification of rare disease variants, including unmasking small mutations with
intermediate risk of AD in PLD3, TREM2, UNC5C, AKAP9, and ADAM10. This review
provides an overview of the genetic basis of AD and the relationship between these risk genes
and the neuropathologic features of AD. An understanding of genetic mechanisms underlying
AD pathogenesis and the potentially implicated pathways will lead to the development of novel
treatment for this devastating disease.
Keywords: Alzheimer’s disease, amyloid precursor protein, genome-wide association studies,
biological pathways, presenilin 1, presenilin 2, neuropathology
Video abstract
Introduction
Currently, there are ~46.8 million dementia cases worldwide, with that number
projected to reach 74.7 million in 2030 and over 131.5 million by 2050.1 Alzheimer’s
disease (AD) is a major public health problem in the world. Health care costs of
dementia in 2015 surpassed $818 billion (USD), and this figure is estimated to be as
high as $2 trillion by 2030.1 AD is the most common form of dementia and one of the
most common diseases in the developed countries. AD is defined clinically by gradual
decline in memory and progressive loss of cognitive functions. Neuropathologically,
AD is characterized by gross cortical atrophy and ventricular dilatation and patho-
logical hallmarks of accumulation of Aβ protein in the form of senile plaques and
Point your SmartPhone at the code above. If you have a intraneuronal tangles of hyperphosphorlylated tau (t) protein. AD is a multifactorial
QR code reader the video abstract will appear. Or use:
and complex disease and leading cause of dementia among elderly people. Although
http://youtu.be/_nbEYWt-BH8
advanced age is the best known risk factor for AD, some individuals may develop
AD at younger age. Hence, based on the time of onset, AD is classified into two
Correspondence: Yang Lü
Department of Geriatrics, The First types.2 Early-onset AD (EOAD), which typically develops before the age 65 years,
Affiliated Hospital of Chongqing and late-onset AD (LOAD) in those older than 65 years. EOAD is caused by rare
Medical University, No 1 Youyi Road,
Yuzhong District, Chongqing 400016, and dominantly inherited mutations in APP, PSEN1, and PSEN2. LOAD has a strong
People’s Republic of China genetic component, and it is also called sporadic AD. Up to 60%–80% of LOAD is
Tel +86 23 8901 1622
Fax +86 23 6881 1487
inheritable, but genetic and environmental factors play a key role in onset, progres-
Email lyu_yang@126.com sion, and severity of disease.3
submit your manuscript | www.dovepress.com Clinical Interventions in Aging 2016:11 665–681 665
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Giri et al Dovepress
The ε4 allele of the APOE gene is the major risk factor candidate genes were tested for AD susceptibility, with
for pathogenesis of LOAD.4,5 Using revolutionizing tech- mostly inconsistent results. The success of this approach
nologies such as genome-wide association study (GWAS), relies on the existing knowledge on disease pathogenesis.
researchers have identified a number of regions of inter- Because of small sample size, inadequately evaluated popula-
est in the genome that may increase a person’s risk for tion groups, and insufficient P-value threshold, most of the
LOAD to varying degrees.6,7 Furthermore, next-generation candidate studies could not be replicated.11
sequencing (NGS) techniques have identified rare suscep-
tibility modifying alleles in different AD genes.8 However, Genome-wide association studies
other causative and risk genes are involved in AD and need The development of microarray technology revolutionized
to be identified to fully elucidate the etiology of AD. In this genetics research, allowing for the simultaneous evaluation of
review, we provide a summary of the genetic basis of both millions of single-nucleotide polymorphisms (SNPs) in thou-
EOAD and LOAD, the relationship between these risk genes sands of samples. Such cheap and comprehensive GWAS
and the pathogenesis of AD. allows one to perform genome-wide association testing in a
hypothesis-free manner. Besides APOE, GWAS has allowed
Types of studies in AD genetics identification of .20 genetic loci associated with increased
Mainly four strategies have governed the field of AD genetics: susceptibility for LOAD.12 GWAS has successfully identified
genetic linkage analysis, study of candidate genes, GWASs, numerous susceptibility genes for AD, but, rare variants will
and NGS technology. Genetic linkage family studies have led not be detectable by GWAS. Thus, the success of GWAS
to the identification of dominantly inherited, rare mutations depends on sample size, frequency of risk alleles, and indi-
in genes of EOAD (APP, PSEN1, and PSEN2). The develop- vidual effect sizes.
ment of whole-genome genotyping by several independent
GWASs has allowed for the study of the involvement of NGS technologies
common variants with low risk in disease. NGS technologies provide fast and cost-effective sequencing
strategies that allow an entire genome to be sequenced
Genetic linkage analysis in ,1 day. NGS technology has important implications in
Linkage analysis was the first milestone in unraveling the understanding the basis of many Mendelian neurological
genetic basis of AD studies of families displaying autosomal conditions and complex neurological diseases that have
dominant inheritance. Genetic linkage studies aim to identify enabled the identification of rare disease variants, including
chromosomal regions associated with disease but do not unmasking small mutations. Recently, NGS has been applied
identify one gene or one mutation associated with a disease. to identify genetic factors in small families with unexplained
Genetic linkage studies in families led to the identification of EOAD. The primary success of NGS in AD has been the
dominantly inherited mutations in APP on chromosome 21q, identification of rare susceptibility modifying alleles in APP,
PSEN1 on 14q, and PSEN2 on 1q that are associated with TREM2, and PLD3.8
EOAD.9 The ε4 allele of the APOE, which is considered as
only one genetic risk factor for LOAD, was also identified EOAD susceptibility genes
with the help of genetic linkage studies.10 Nonetheless, link- Studies of families with autosomal dominant patterns
age mapping has been very useful in identifying monogenic of inheritance were a cornerstone in understanding the
traits in EOAD, but it has largely failed to identify risk genetics of AD. Three genes are considered the main risk
factors in LOAD, probably due to the complex trait with factors for EOAD: APP on chromosome 21q, PSEN1 on
unidentified variants. 14q, and PSEN2 on 1q that are associated with EOAD
(Table 1). To date, .270 highly penetrant mutations have
Study of candidate genes been described in these genes that cause familial AD and
In candidate gene studies, genetic variants of people with many more are discovered each year13 (http://www.molgen.
a particular disease are genotyped and compared with a ua.ac.be/admutations/).
similar group of healthy individuals. Susceptibility genes
are revealed when case and control frequencies differ sig- APP
nificantly. Candidate gene approach elucidated that APOE The gene encoding APP is located on chromosome 21q21.3.
risk alleles are firmly implicated in LOAD. Over 1,000 The three isoforms, APP751, APP770, and APP695, are
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Dovepress Genes associated with AD
Table 1 Genes implicated in risk of early-onset Alzheimer’s disease

Gene symbol Location Function Pathway References
APP 21q21.3 Neuronal development, Synaptic formation APP processing 13–15,18
and repair, β-Amyloid production
PSEN1 14q24.3 γ-Secretase activity, Intracellular signaling, APP processing 9,26,27
β-Amyloid production
PSEN2 lq42.13 γ-Secretase activity, β-Amyloid production, APP processing 13,27,36
Synaptic plasticity
produced by splicing of APP. The major isoform found in β-Amyloid plaques and neurofibrillary tangle were found in
brain is APP695.14 APP is proteolytically cleaved following the American family, with the absence of amyoid angiopathy
nonamyloidogenic or amyloidogenic pathway by three or Lewy bodies.21 Arctic mutation (E693G) occurs in the
enzymes, known as α-, β-, and γ-secretases. Proteolysis coding region of Aβ domain. This mutation fails to alter total
of APP by α- and γ-secretases results in nonpathogenic Aβ level or the ratio of Aβ42/Aβ40. Arctic mutation results
fragments (sAPPα and α-C-terminal fragment) in non- in increased aggregation rate of mutant peptide.22 Brain
amyloidogenic pathway. In the amyloidogenic pathway, imaging showed no signs of strokes or vascular lesions but
proteolysis of APP by β-secretase and γ-secretase results in neuritic plaques and neurofibrillary tangles consistent with a
two major Aβ species that include sAPPβ and β-CTF.15 The diagnosis of AD were seen in one mutation carrier.23 Flem-
action of γ-secretases on β-CTF generates Aβ, which forms ish mutation (A692G) falls within the region of Aβ domain
a key component of amyloid plaques known as extracellu- and increases the level of Aβ42 and Aβ40 by twofold to
lar fibrils in AD brain.16 To date, 49 APP mutations in 119 fourfold, affecting γ-secretase activity for Aβ production.
families are known to cause AD.13 Most of the APP muta- Flemish mutation results in Aβ deposition in the blood ves-
tions are dominantly inherited but two recessive mutations, sels of the brain and senile plaques.24 Jonsson et al25 found a
A673V and E693Δ have been reported to cause EOAD.17 The rare mutation (A673T) in the APP gene that showed a strong
clustering of most pathogenic APP mutations either adjacent protective effect against AD.
to or within the cleavage sites of β- and γ-secretase (exons 16 Abovementioned examples show that altered APP
and 17 of APP) shows that they might be involved in AD processing and Aβ accumulation are key in the AD
pathogenesis.13,18 Swedish APP Mutation (KM670/671NL) pathogenesis.
is a double point mutation located at the N-terminus of
the Aβ domain adjacent to the β-secretase site in which PSEN1
lysine–methionine is replaced by asparagine–leucine. In PSEN1 gene is located on chromosome 14q24.3, and it is a
Swedish mutation, total Aβ level increases by twofold vital component of the γ-secretase complex, which cleaves
to threefold, thus affecting the efficiency of β-secretase APP into Aβ fragments. PSEN1 is localized primarily to
cleavage.19 In a case with Swedish mutation, autopsy revealed the endoplasmic reticulum and helps in protein processing.
cortical atrophy, enlargement of the cerebral ventricles, To date, 215 pathogenic mutations have been identified in
and sulcal widening. Studies have shown that patients with PSEN1, of which .70% mutations occur in exons 5, 6, 7,
Down syndrome (trisomy 21) develop AD pathology ear- and 8.13 Mutations in PSEN1 account for up to 50% of EOAD,
lier than the normal person.17,20 Thus, AD pathology may with complete penetrance and early age of onset. Mutant
be related to overexpression of APP. Along with Swedish γ-secretase increases Aβ42 level while it decreases Aβ40
APP Mutation, Tottori mutation (Asp678Asn) and Leuven level, leading to an increase in the Aβ 42/40 ratio. Studies
mutations (Glu682Lys) are located at the N-terminus of the have shown that Aβ42 is more amyloidogenic and more prone
Aβ domain adjacent to the β-secretase site. London muta- to aggregate in brain than Aβ40.9,26,27 Morphologic variants in
tion (V717I) is one of the most common APP mutations Aβ plaques due to PSEN1 mutations may result in cotton wool
worldwide. APP mutation at or after C-terminus of the Aβ plaques. Cotton wool plaque is formed by large rounded Aβ
domain alters the γ-secretase function with increased Aβ42/ deposits, and it tends to be immunopositive for Aβ42 rather
Aβ40 ratio by increasing Aβ42 levels and decreasing Aβ40 than for Aβ40.28–30 The vast majority of PSEN1 mutations are
levels. Neuropathological findings in an English family missense mutations, but a few insertion and deletions have
were cortical Lewy bodies and mild amyloid angiopathy. also been detected. Neuronal loss of 30% in the hippocampal
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CA1 region, decreased synaptic plasticity, and 18% of LOAD susceptibility genes
hippocampus atrophy was demonstrated by Breyhan et al31 LOAD is genetically far more complex than EOAD with the
due to the intraneuronal accumulation of Aβ peptides and possible involvement of multiple genes and environmental
fibrillary accumulation species. In addition to their role in factors. Most LOAD cases are sporadic with no family
γ-secretase activity, PSEN1 mutations may compromise history of the disease. Before the era of large-scale GWAS,
neuronal function, affecting GSK-3β activity and kinesin-I- ε4 allele of the APOE gene was the only well-established risk
based motility, thus leading to neurodegeneration.32 factor for the pathogenesis of LOAD, but with technological
advances, researchers have identified a number of regions of
PSEN2 interest in the genome that may increase a person’s risk for
PSEN2 gene is located on chromosome 1q31-q42, and it LOAD to varying degrees. It was striking to note that most
is very similar in structure and function to PSEN1. PSEN2 of the genes identified by GWAS that could be linked with
mutations are very rare, and to date 13 pathogenic PSEN2 the Aβ cascade or tau pathology roughly cluster within three
mutations have been detected in 29 families.13 PSEN2 is pathways (Figure 1). We will briefly describe the known
a main component of the γ-secretase complex along with genes of LOAD, biological pathways, and mechanisms that
PSEN1, nicastrin, Aph-1, and PEN-2.33 PSEN2 mutation might be relevant to AD biology.
alters the γ-secretase activity and results in increase in the
Aβ 42/40 ratio in similar manner to the PSEN1 mutation.9,26,27 Genes involved in cholesterol metabolism
PSEN2 mutations carriers have older age of onset with a The genes implicated in cholesterol metabolism are APOE,
wide range from 39 years to 75 years. Neuritic plaque for- SORL1, ABCA7, and CLU6,37–39 (Table 2). Solomon et al40
mation and neurofibrillary tangle accumulation may be seen demonstrated that having high cholesterol levels in midlife
as neuropathological changes in some people with PSEN2 increased the risk of developing AD in late life.
mutations.34 Park et al35 demonstrated that β-secretase activity
is enhanced by PSEN2 mutation, through reactive oxygen APOE gene
species-dependent activation of extracellular signal-regulated The APOE gene, located on chromosome 19q13.2, is the
kinase. Although, PSEN2 shows close homology to PSEN1, strongest genetic risk factor for LOAD. APOE protein is
but less amyloid peptide is produced by PSEN2.36 the major cholesterol carrier in the brain. There are three
Lipid
Inflammatory metabolism
response CLU
TRE , ABC E
M2 A PO
, EP 7, CD A
HA 33, C 7, G2
ME
1 R1, C A
, DS
F AB L1
HLA 2C, M R
-DR S4A , SO
B5/ , LU
HLA INPP C
-DR 5D,
B1 AD
CD2AP, PICALM
SORL1, BIN1
Endocytosis
Figure 1 Major pathways involved in AD and affected genes.

Abbreviation: AD, Alzheimer’s disease.

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Table 2 Common and rare variants associated with Alzheimer’s disease

Gene Chromosome SNP Function Pathway References
APOE 19q13.2 Lipid transport Lipid metabolism 41–44
Synaptic vesicle endocytosis
Cytoskeletal dynamics
CLU 8p21-p12 rs11136000 Synapse turnover Cholesterol metabolism and 37,66,67
Complement regulation immune response
Chaperone protein
ABCA7 9p13.3 rs3764650 Phagocytosis Lipid metabolism 72,74,78
rs3752246 Lipid homeostasis Immune response
SORL1 11q23.2-q24.2 rs12285364 Endocytosis Endocytosis 79,81,88
Receptor for APOE Lipid metabolism
Processing of APP
CR1 1q32 rs3818361 Amyloid β clearance Immune response 91,92,94
rs6656401 Complement activation
CD33 19q13.3 rs3865444 Clathrin-mediated endocytosis Immune response 97,101
rs3826656 Cell signaling
MS4A 11q12.2 rs610932 Signal transduction Immune response 102,103
rs670139 Immune function
rs4938933
TREM2 6p21.1 rs75932628 Inflammatory response Immune response 104,107,110
BIN1 2q14.3 rs744373 Synaptic vesicle endocytosis Synaptic vesicle endocytosis 114,118
rs7561528 APP trafficking
CD2AP 6p12 rs9296559 Receptor-mediated endocytosis Endocytosis 119,120,122
rs9349407 Cytokinesis Synapse function
PICALM 11q14 rs3851179 Clathrin-mediated endocytosis Endocytosis 114,123,125
rs541458 Synapse function
EPHA1 7q34 rs11771145 Synaptic development Immune response 38,132,133
rs11767557 Immune function
Neural development
HLA-DRB5/HLA-DRB1 6p21.3 rs9271192 Immune function Immune response 38,135,137
Histocompatibility
INPP5D 2q37.1 rs35349669 Cytokine signaling Immune response 38,138
Immune function
MEF2C 5q14.3 rs190982 Myogenesis Immune response 140,141
Synapse formation Hippocampal synaptic function
CASS4 20q13.31 rs7274581 Cell migration Cytoskeletal function and axonal 134,142,144
rs6024870 Cell adhesion transport
rs16979934
PTK2B 8p21.1 rs28834970 Calcium homeostasis Hippocampal synaptic function 146,147
MAP kinase signaling
NME8 7p14.1 rs2718058 Ciliary function Axonal transport and cytoskeletal 149,150
Neuronal cell proliferation function
ZCWPW1 7q22.1 rs1476679 Epigenetic regulation Epigenetic regulation 153,154
Neural development
CELF1 11p11 rs10838725 mRNA editing Cytoskeletal function and axonal 144,155
Pre-mRNA splicing transport
FERMT2 14q22.1 rs17125944 Cell–cell adhesion Tau pathology 134,160
Angiogenesis Angiogenesis
SLC24A4/RIN3 14q32.12 rs10498633 Cell signaling Synapse function endocytosis 166,169
Neural development
DSG2 18q12.1 rs8093731 Cell–cell adhesion 38,172,173
PLD3 19q13.2 rs145999145 Signal transduction Lipid metabolism 174,175
Epigenetic modification
UNC5C 4q22.3 rs137875858 Neural development 177
AKAP9 7q21-q22 rs144662445 Signal transduction 183,184
rs149979685
ADAM10 15q22 rs2305421 Hippocampal neurogenesis 186,187
Cell adhesion
Abbreviation: SNP, single-nucleotide polymorphism.

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common alleles of APOE called ε2, ε3, and ε4 alleles. APOE periphery and the brain.65 CLU is situated on chromosome
ε4 increases LOAD risk, whereas APOE ε2 is associated with 8p21-p12. CLU is hypothesized to act as an extracellular
decreased LOAD risk.41–44 There is a threefold increased risk chaperone that plays an important role in lipid transport,
of AD by one copy of APOE ε4 and 12-fold by two APOE complement regulation, apoptosis, sperm maturation, endo-
ε4 alleles. APOE is involved in the control of inflammation, crine secretion, and membrane protection.66,67 AD patients
cholesterol metabolism, lipid transport, synaptic function, have elevated levels of CLU in the frontal cortex and hip-
neurogenesis, or the generation and trafficking of APP and pocampus.68 CLU concentration is increased in the CSF
Aβ.45–47 In the study of large Colombian kindred, APOE ε4 of patients with AD, suggesting its utility as a prognostic
was associated with earlier onset of dementia in individuals or diagnostic biomarkers in AD. Plasma CLU level was
with PSEN1 mutation.48 More recently, Vélez et al49 reported shown to be linked with brain atrophy, disease severity,
ApoE2 allele delays age of onset for carriers of the Paisa and clinical progression in AD patients. AD patients with
mutation (PSEN1 E280A). The mechanism that underlies increased CLU mRNA expression deteriorate faster than
the link between APOE4 genotype and AD is complex. normal.69,70 Similar to APOE, CLU is present in amyloid
Studies in humans and transgenic mice showed that APOE plaques, binds to Aβ peptides, and interacts with Aβ40
influences Aβ clearance, aggregation, and deposition in an and Aβ42. Thus CLU might play an important role in AD
isoform-dependent manner.50–52 Studies suggest that ApoE4 pathology. Recently, Deming et al71 found that CLU levels
inhibits Aβ clearance and is less efficient in mediating Aβ were significantly associated with AD status and CSF tau/
clearance compared with ApoE3 and APOE2. ApoE4 also Aβ ratio, thus influencing the immune system and neuro-
contributes to AD pathogenesis by Aβ-independent mecha- genesis in AD. CLU suppresses Aβ deposition, inhibits the
nisms that involve synaptic plasticity, cholesterol homeo- complement system to prevent inflammation, and decreases
stasis, neurovascular functions, and neuroinflammation. apoptosis and oxidative stress in AD. These findings gener-
In APOE4 carriers, there is accelerated Aβ deposition as ally support a biochemical role for CLU in the development
senile plaques compared with noncarriers.53,54 Recently, of AD pathogenesis.
Dorey et al55 showed that APOE isoforms differentially
regulate and modify the Aβ-induced inflammatory response ABCA7
in neural cells in AD, with ApoE2 suppressing and ApoE4 ABCA7, located on chromosome 19p13.3, has recently been
promoting the response. Levels of total tau (t-tau) and phos- identified as a strong genetic locus associated with LOAD in
phorylated tau (p-tau) 181 were increased in AD patients who GWASs.37,72 ABCA7 is a member of the ATP-binding cas-
were APOE4 homozygotes.56 Conversely, lower cerebrospi- sette genes, and its expression was detected in hippocampal
nal fluid (CSF) p-tau and t-tau concentrations and decreased and microglia cells in the brain.73 ABCA7 mediates transport
rate of hippocampal atrophy were seen in APOE2 carriers. of high-density lipoprotein cholesterol, effluxes lipids from
This shows that APOE ε2 is associated with decreased AD cell into lipoprotein particle, and generates phospholipids.
pathology.57 APOE2 has higher affinity for Aβ than does It can also play a vital role in cholesterol homeostasis and
APOE4.58 Therefore, APOE2 may be more efficient than the immune system. Meta-analyses of all data provided
APOE4 at clearing Aβ fragments from the extracellular compelling evidence that SNPs rs3752246 and rs3764650
space.59 Neuroimaging study of APOE ε4 carriers showed near ABCA7 have been associated with LOAD.38,74 Recently,
gray matter volume decline with age, elevated hippocam- ABCA7 variant SNP (rs115550680) was found to nearly
pal atrophy, increased amyloid load, impaired glucose double the risk of LOAD in African-Americans.75 ABCA7
metabolism, and cerebral amyloid angiopathy with increased also regulates phagocytosis by macrophage uptake of Aβ
microbleeds.60–63 and mediates processing of APP.76,77 The recent study by
Steinberg et al78 in Icelandic population identified ABCA7
CLU as the most significant gene for AD. Studies in adult mice
The clusterin (CLU) gene has been identified as an impor- showed that ABCA7 is expressed most abundantly by
tant risk locus for AD in more than two GWASs.37,64 In macrophages (ie, tenfold higher than neurons), and Aβ is
these GWASs, three SNPs within CLU (rs11136000, accumulated in brain of ABCA7-deficient mice.76 Emerging
rs2279590, and rs9331888) showed statistically significant data suggest that ABCA7 could be associated with AD via
association with AD. CLU, also known as apolipoprotein various pathways, possibly including Aβ accumulation, lipid
J, is an apolipoprotein that is widely expressed in both the metabolism, and phagocytosis.

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SORL1 of AD later in life.95 CR1 plays a key role in AD pathogenesis

SORL1 (also known as SorLA and LR11) is located on chro- via reducing activation of complement cascade activity. CR1
mosome 11q23.2-q24.2, and it is a member of the Vsp10p variant is associated with increased CSF Aβ42 levels, and
domain receptor family and is involved in intracellular trans- some variants lead to vascular amyloid deposition.96,97 CR1
port and processing of APP, resulting in decreased production mRNA is involved in the formation of neurofibrillary tangles
of Aβ peptide.79,80 Although the actual functional risk loci and thus results in cognitive decline.70
within the SORL1 gene still remain unknown, studies have
showed that SORL1 plays a key role in AD susceptibility.81–83 CD33
Disruption of SORL1 has also been shown to influence Aβ CD33 is located on chromosome 19q13.3, and it is a type I
pathway and tau-related cellular processes.84,85 Significant transmembrane protein, which belongs to the sialic acid-
associations between SORL1 genetic variants and AD have binding immunoglobulin-like lectins, and it is expressed
been reported in several ethnic groups.86,87 SORL1 risk vari- on myeloid cells and microglia. CD33 plays an impor-
ants have also been associated with hippocampal atrophy, and tant role in mediating cell–cell interaction, facilitates
altered CSF Aβ level, suggesting its potential role in LOAD clathrin-independent endocytosis, inhibits immune cell func-
pathogenesis.88 The current data suggest that underexpression tions, and regulates cell growth and survival, via induction
of SORL1 leads to overexpression of Aβ, which has been of apoptosis.98,99 Recent GWASs have identified CD33 as a
associated with a higher risk of developing AD.84,89 SORL1 strong genetic locus associated with LOAD. The two SNPs
also mediates APP processing via endocytotic pathways at the CD33 gene cluster, rs3865444 and rs3826656, have
and plays a key role in Aβ production.84 Meta-analysis of been associated with LOAD.39,72 In AD patients, the minor
the association between variants in SORL1 and AD has allele of the CD33 SNP rs3865444 was associated with reduc-
identified that SNP rs12285364 was significantly associated tions in both CD33 level and amyloid plaque burdens in the
with increased risk of AD.90 brain.100 There is positive correlation between CD33 expres-
sion in microglia with plaque burden and declined cognitive
Genes involved in immune response function. Bradshaw et al101 demonstrated that the CD33 risk
Involvement of the immune system in the pathogenesis of allele rs3865444 increases CD33 expression in monocytes
LOAD was revealed in several GWASs. Neuroinflammation and is associated with increased amyloid pathology in
is a pathological hallmark of AD. LOAD genes implicated in patients with AD. CD33 contributed to the pathogenesis of
immune response are CR1, CD33, MS4A, ABCA7, EPHA1, LOAD by impairing microglia-mediated clearance of Aβ.
TREM2, and CLU6,37–39,72 (Table 2). Furthermore, the increased Aβ clearance and reduced Aβ
levels in vitro and in vivo are due to deletion of CD33.
CR1
CR1 (also known as C3b/C4b receptor or CD35) is located MS4A
on chromosome 1q32, and it is a member of the receptors of The MS4A gene is located on chromosome 11q12.2, and it
complement activation family. CR1 is a single-chain type I encodes protein that contains at least four potential trans-
transmembrane glycoprotein comprising four main structural membrane domains, two extracellular loops with cytoplasmic
domains and mainly expressed on erythrocytes, leukocytes, N- and C-terminal domain, and one intracellular loop. MS4A
and splenic dendritic cells.91 CR1 acts as a receptor in clas- genes are highly expressed in hematopoietic cells such as
sical pathway and alternative pathway; CR1 on phagocytes myeloid cells and monocytes. Although MS4A genes are
facilitates the uptake and removal of immune complexes; CR1 poorly characterized, MS4A1 (CD20), MS4A2 (FcεRIβ),
components have neuroprotective effect in AD. Thus, CR1 and MS4A3 (HTm4) play an important role in immunity.102
functions as a complement regulatory protein and helps in MS4A1 was found to interact with activated B-cell antigen
immune regulation.92,93 In recent GWASs, SNPs in CR1 have receptor complex to regulate calcium influx. Dysregulation
been associated with LOAD risk.38,64,72 It has been reported that of intracellular calcium signaling plays an important role
SNPs rs3818361 and rs6656401 in CR1 are associated with in the pathogenesis of AD. Recent GWASs have identified
increased risk of AD.64 SNP rs1408077 was associated with three members of MS4A family; MS4A4A, MS4A4E, and
plaque load in the brain of patients with AD.94 The deposition MS4A6E associated with LOAD.6,103 To date, many SNPs
of smaller local gray matter volume in the entorhinal cortex of have been identified in LOAD GWASs, including rs670139
carriers of the CR1 rs6656401 might lead to an increased risk in MS4A4E, rs4938933, and rs1562990 located within the

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region between MS4A4E and MS4A4A, and rs610932 and protein.112 More extensive brain atrophy was seen in AD
rs983392 in MS4A6A.6,103 Aside from rs983392 in MS4A6A, patients who carry a TREM2 mutation than noncarriers.113
the SNP rs4938933 was also associated with reduced AD
risk, while SNPs rs670139 and rs610932 were associated Genes involved in endocytosis/vesicle-
with increased LOAD risk. Recently, Karch et al70 found that mediated transport
MS4A6A expression level and minor allele of rs670139 in Endocytosis is a critical process in synaptic transmission and
MS4A6E were associated with increased Braak tangle and response to neural damage. In recent LOAD GWASs, several
plaque in AD patients. MS4A families affect AD progression genes were revealed, which are involved in regulating endo-
and pathogenesis including Aβ generation, tau phosphory- cytosis, including BIN1, CD2AP, PICALM, EPHA1, SORL1,
lation, and apoptosis by regulating calcium homeostasis. etc6,37,38,64,72 (Table 2). Most of these genes are involved in APP
Elevated levels of MS4A4A and MS4A6A may cause det- trafficking, which plays a key role in AD pathogenesis.
rimental effect on LOAD pathogenesis.
BIN1
TREM2 BIN1 is located on chromosome 2q14.3, and it has more
TREM2 gene is located on chromosome 6q21.1, which than ten isoforms produced by alternative splicing. BIN1
encodes a single-pass type I membrane protein made up of is implicated in synaptic vesicle endocytosis, intracellular
an extracellular immunoglobulin-like domain, a transmem- APP trafficking, immune response, apoptosis, and clathrin-
brane domain, and a cytoplasmic tail, which interacts with mediated endocytosis.114,115 The BIN1 gene locus was initially
DAP12 or TYROBP for its signaling function.104 TREM2 identified as having a possible association with AD in large
is one of the highly expressed cell surface receptors on GWASs.6,116 Several independent candidate gene studies have
microglia that facilitates phagocytosis and downregulation replicated and confirmed that SNPs rs744373 and rs7561528
of inflammation. TREM2 is expressed throughout the central located near BIN1 coding region are associated with LOAD
nervous system, with highest concentrations in white matter risk. Neuroimaging measures have shown that BIN1 risk
and lowest concentrations in the cerebellum.7 Jonsson et al104 variant (SNP rs7561528) was associated with thickening
performed whole-genome sequencing in Icelandic population of temporal pole and entorhinal cortex.117 In AD patients,
and reported that a missense mutation R47H (rs75932628) upstream of SNP rs59335482 within the BIN1 was associ-
within TREM2 was strongly associated with AD with an odds ated with increased tau loads but not with Aβ, suggesting
ratio as strong as that for APOE ε4. Similar associations were that BIN1 might modulate tau-related AD pathogenesis.118
found in cohorts from the US, Germany, the Netherlands, BIN1 knockdown suppresses tau-mediated neurotoxicity;
and Norway.104–106 Missense mutation R47H in TREM2 has therefore, BIN1 can act as a therapeutic target for AD. Little
been reported to increase LOAD risk in a meta-analysis of is known about the role of BIN1 in neurodegeneration.
three imputed data sets of GWASs (EADI, GERAD, and Therefore, further investigation is required to reveal the role
ANM).105 Among six additional variants found by Guerreiro of BIN1 in AD pathogenesis.
et al,107 three variants (Q33X, Y38C, and T66M) had been
related to a frontotemporal dementia-like syndrome without CD2AP
bone involvement in the homozygous state. Recent study CD2AP is an 80 kDa cytoplasmic scaffolding protein located
by Jin et al106 found 16 rare coding variants in TREM2, of on chromosome 6p12, and it is responsible for regulation
which two variants R47H and R62H were associated with of the cytoskeletal structure. CD2AP is also involved in
increased LOAD risk. A homozygous mutation in TREM2 receptor-mediated endocytosis, cell adhesion, intracellular
was associated with an autosomal recessive form of early- trafficking, cytokinesis, and apoptosis.119 Recently, CD2AP
onset dementia called Nasu–Hakola disease.108,109 These was detected as a risk factor for AD by several GWASs.6,38,72
patients have multifocal bone cysts predisposing to patho- GWASs of LOAD have identified SNPs rs9296559 and
logical fracture. Patients with heterozygous loss-of-function rs9349407 in CD2AP as AD susceptibility loci. CD2AP
mutations have increased risk for LOAD. 104,105 TREM2 is expressed in brain and in AD patients. SNP rs9349407
variant R47H increased risk of neurodegenerative disorders is associated with increased neuritic plaque pathology.120
such as frontotemporal dementia, Parkinson’s disease, and CD2AP interacts with the presynaptic transmembrane protein
amyotrophic lateral sclerosis.107,110,111 TREM2 R47H variant called neurexin and thus helps in vesicle trafficking and cell
showed accelerated CSF tau and hyperphosphorylated tau adhesion. A recent APP transgenic mouse model revealed

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that suppressing CD2AP expression altered Aβ levels and and rs11767557 were documented to be associated with
decreased Aβ42/Aβ40 ratio in vitro. In vivo CD2AP was decreased LOAD risk.6,38,72 Recently, Wang et al133 demon-
associated with subtle alteration in the level of Aβ.121 Pre- strated that EPHA1 (rs11771145) genetic variant reduced
vious GWASs have failed to show significant association LOAD risk by functional modification of hippocampus,
between SNP rs9349407 and CD2AP in Chinese, Japanese, lateral occipitotemporal, and inferior temporal gyri in AD.
African-American, Canadian, and European populations.6,72 EPHA1 is implicated in immune function, synaptic plasticity,
Recently, Chen et al122 reported significant association chronic inflammation, and cell membrane processes.
between CD2AP rs9349407 polymorphism and AD in East
Asian, American, Canadian, and European populations. Other genes implicated in LOAD
Recent meta-analysis of GWASs identified additional genes
PICALM implicated in LOAD: HLA-DRB5/HLA-DRB1, INPP5D,
The PICALM gene is situated on chromosome 11q14, and MEF2C, CASS4, PTK2B, NME8, ZCWPW1, CELF1,
it is ubiquitously expressed with particularly high levels in FERMT2, SLC24H4-RIN3, and DSG26,37–39 (Table 2).
neurons. Similar to BIN1, PICALM is also implicated in Functions of most of these genes are unknown or poorly
clathrin-mediated endocytosis and intracellular trafficking. characterized. These genes may be involved in different pos-
The SNPs rs3851179 and rs541458 were found to be associ- sible pathways.134 HLA-DRB5/HLA-DRB1, INPP5D, and
ated with LOAD in GWASs for AD risk factors.37,38 PICALM MEF2C are involved in immune response and inflammation.
plays a key role in synaptic transmission by the trafficking NME8, CELF1, and CASS4 are implicated in cytoskeletal
of VAMP2. In cell culture models and APP/PS1 mice, Xiao function and axonal transport. PTK2B is involved in hip-
et al123 revealed that PICALM facilitates Aβ production by pocampal synaptic function. ZCWPW1 is an epigenetic
internalizing APP but knockdown of PICALM influenced regulator. FERMT2 is involved in tau pathology and angio-
APP internalization and decreased Aβ production and genesis. SLC24H4-RIN3 has possible cardiovascular risk.
release. Therefore, PICALM was regarded as a key regula-
tor of brain Aβ production, amyloid plaque load, and APP HLA-DRB5/HLA-DRB1
internalization. SNP rs3851179 in PICALM has been associ- HLA-DRB5/HLA-DRB1 is situated on chromosome 6p21.3,
ated with thickening of entorhinal cortex and hippocampal and it is a member of the major histocompatibility complex
degeneration.117,124 Schjeide et al125 have revealed that the class II. HLA-DRB5/HLA-DRB1 plays an important role
risk allele of PICALM SNP rs541458 was associated with in immune response and histocompatibility.135 HLA-DRB5/
decreased levels of CSF Aβ42 in a dose-dependent manner. HLA-DRB1 is expressed on microglia in the brain. An asso-
Studies have failed to find any associations between PICALM ciation of HLA-DRB1 rs9271192 with LOAD was reported
SNPs and tangles, but the PICALM expression was increased in a meta-analysis of 74,046 individuals.38 HLA-DRB1/
in the frontal cortex in AD.126 PICALM plays an important DRB5 polymorphism was associated with multiple sclero-
role in Aβ blood–brain barrier transcytosis and clearance.127 sis.136 Recent GWASs have also shown association between
PICALM also plays a role in autophagy and tau clearance.128 rs3129882 polymorphism in intron 1 of HLA-DRA gene
Treusch et al129 revealed that PICALM modulates Aβ-induced and Parkinson’s disease.137 HLA-DRB5/HLA-DRB1 is
toxicity in a yeast model by impairing endocytosis. Morgen also implicated in antigen presentation, inflammation, and
et al130 showed that synergistic interaction of PICALM complement system.
(rs3851179) and APOE ε4 allele was associated with declined
cognitive function and brain atrophy in AD. INPP5D
INPP5D is located on chromosome 2q37.1, and it encodes
EPHA1 the SH2-containing inositol 5-phosphatase 1 (SHIP1).
EPHA1, located on chromosome 7q34, is a member of the INPP5D, also known as SHIP1, is a key regulator of cytokine
tyrosine kinase family and plays a crucial role in synapse for- signaling. The SNP rs35349669, near INPP5D, is associated
mation and development of the nervous system.131 EPHA1 has with increased LOAD risk.38 In addition to the hematopoietic
high affinity for membrane-bound ligand, ephrins-A1, which compartment, SHIP is also present in osteoblasts, mature
regulates bidirectional signaling to adjacent cells via synapse granulocytes, and macrophages. Recently, Chen et al138 found
formation.132 EPHA1 is widely expressed in differentiated that inhibitor of INPP5D can be used in acute lymphoblastic
epithelial cells and lymphocytes. EPHA1 SNPs rs11771145 leukemia to overcome drug resistance. Diseases such as

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cancer, inflammatory diseases, diabetes, atherosclerosis, Fyn to the AD risk gene product, Pyk2, was blocked by Fyn
and AD may be treated with the help of SHIP modulation.139 kinase inhibitor, AZD0530, in Alzheimer mice. Fyn kinase
SHIP is implicated in multiple signaling pathways, such as inhibitions improved the learning and memory impairment
phosphatidylinositol 3-kinase (PI3K) pathway, and PI3K is in Alzheimer mice.148 There is a strong interaction between
central to signal transduction pathway. calcium homeostasis and NEDD9 and PTK2B.145 Hence,
PTK2B might be of immense value to investigate its func-
MEF2C tional role in the context of AD.
MEF2C is located on 5q14.3, and it encodes a member of
the MADS box transcription enhancer factor 2. MEF2C is NME8
involved in myogenesis, neurogenesis, and development NME8 is located on chromosome 7p14.1, and it encodes
of multiple organ system. A GWAS in 74,046 individuals a protein with an N-terminal thioredoxin domain and
revealed that SNP rs190982 near MEF2C is associated C-terminal nucleoside diphosphate kinase domains. NME8
with increased LOAD risk.38 MEF2C mutations are asso- is member of NM23 family, and it is involved in proliferation
ciated with severe mental retardation, seizure, cerebral and differentiation of neuronal cells.149 SNP (rs2718058)
malformation, and stereotypic movements.140 In addition to adjacent to NME8 was associated with decreased LOAD
hematopoietic role, MEF2C regulates B cell proliferation. risk.38 Liu et al150 found that there is positive correlation
MEF2C is a regulator of adipose metabolism in vertebrates, between NME8 (rs2718058) genetic variants and AD patho-
and it is a core transcriptional component of the innate logical features such as cognitive decline, the elevated tau
immune response of the adult fly.141 levels in CSF, and the hippocampus atrophy. NME8 has also
been associated with primary ciliary dyskinesia and knee
CASS4 osteoarthritis.151,152
CASS4 is located on chromosome 20q13.31, and it is also
known as HEPL. CASS4 is widely expressed in the lung and ZCWPW1
spleen, and CASS4 mRNA expression is highest in leuke- Zinc finger CW (zf-CW) domain consists of 60 amino acids.
mia cell lines.142 Although the exact function of CASS4 is Although the function of zf-CW domain is unknown, it might
unknown, it appears to play an important role in focal adhe- be regarded as a new histone modification reader. zf-CW
sion kinase regulation, cellular adhesion, cell migration, and domain is found in methylation or demethylation enzymes and
motility.142 In a meta-analysis of 74,046 individuals, CASS4 several other proteins.153 ZCWPW1 is located on chromosome
SNP rs7274581 has been associated with decreased LOAD 7q22.1, and it may be involved in epigenetic regulation by
risk.38 Recently, CASS4 was associated with neuritic plaques histone modification.153 Rosenthal et al144 reported genome-
burden and neurofibrillary tangles in brains with AD.143 The wide significant SNPs (ZCWPW1/rs1476679) associated with
SNPs rs6024870 and rs16979934 near CASS4 were identi- LOAD. Protective LOAD allele SNP rs1476679 at ZCWPW1
fied as AD risk alleles in GWASs in LOAD.134,144 CASS4 affects binding of CTCF and RFX3 in K562 by acting expres-
plays a vital role in inflammation, calcium signaling, and sion quantitative trait loci for GATS, PILRB, and TRIM4.143
microtubule stabilization, suggesting that CASS4 might be Recently, ZCWPW1/PILRB locus mapping showed that SNP
associated with AD pathogenesis.145 rs1476679 was associated with decreased level of PILRB and
LOAD risk in one group, while in another group with increased
PTK2B levels of PILRB and no association with LOAD.154
PTK2B (also known as PYK2, Cak2β, or RAFTK) is located
on chromosome 8p21.1, and it encodes a cytoplasmic pro- CELF1
tein tyrosine kinase, which is involved in calcium-induced CELF1, located on chromosome on 11p11, is a member of
regulation of ion channels and activation of the MAP kinase the CELF/BRUNOL protein family that is implicated in
signaling pathway.146 PTK2B is highly expressed in the central the regulation of pre-mRNA alternative splicing, mRNA
nervous system. SNP in PTK2B (rs28834970) was associated editing, and mRNA translation.155 The SNP rs10838725
with LOAD risk in 74046 individuals from diverse ethnici- located in an intron of the CELF1 gene was associated
ties.38 SNP–SNP interaction between rs28834970–rs6656401 with LOAD risk.144 Recent studies have shown that CELF1
(PTK2B-CR1) and rs28834970–rs6656401 (PTK2B-CD33) is overexpressed in many human malignant tumors, and
was associated with increased LOAD risk. 147 Recently, it is also upregulated in glioma and promotes glioma cell
Kaufman et al demonstrated that downstream signaling from proliferation.156,157 The role of CELF1 in myotonic dystrophy

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type 1 (DM1), cytoskeletal function, and axonal transport was as whole-exome sequencing and whole-genome sequencing
also reported.158 LOAD susceptible gene CELF1 mediates have proven to be very powerful techniques to identify novel
tau toxicity in drosophila.159 genes with low-frequency variants associated with both
EOAD and LOAD. Using novel sequencing technologies,
FERMT2 the following genes have been identified: TREM2, PLD3,
FERMT2 (also known as kindlin-2, KIND2) is located on UNC5C, AKAP9, and ADAM10104,107,174 (Table 2).
chromosome 14q22.1, and it regulates integrin activation by
binding to the integrin β cytoplasmic tail via a C-terminal PLD3
domain.160 Kindlin-2 was involved in the progression of PLD3 is located at chromosome 19q13.2, and it encodes a
non-small-cell lung cancer, breast cancer, and gastric nonclassical PLD3 protein associated with the endoplasmic
cancer.161–163 Kindlin-2 is also essential for myogenesis and reticulum. PLD3 is highly expressed in brain (such as frontal,
angiogenesis.164,165 The SNP rs17125944 located in FERMT2 temporal, and occipital cortices and hippocampus), and it
gene was associated with LOAD risk.134 Study in flies showed may be involved in neurotransmission, cell differentiation,
that tau toxicity is modulated by altered expression of CELF1 epigenetic modifications, and signal transduction.175 Whole-
and FERMT2, suggesting a potential role of FERMT2 in AD exome sequencing performed by Cruchaga et al175 found that
pathogenesis.159 the rare missense variant V232M (rs145999145) in exon 7 of
PLD3 was associated with increased risk of LOAD. PLD1
SLC24A4/RIN3 and PLD2 have been associated with Aβ pathology; little is
SLC24A4 (also known as NCKX4) is located on chro- known about the actions of PLD3 in AD. Cruchaga et al175
mosome 14q32.12, and it encodes a member of the revealed that PLD3 may be involved in APP processing
potassium-dependent sodium/calcium exchanger. SLC24A4 and is overexpressed in brain tissue from AD patients.174
is associated with neural development, hair color, and skin Satoh et al176 found that accelerated accumulation of PLD3
pigmentation.166,167 SNP rs10498633 located at intron of on neuritic plaques in AD brains may be associated with AD
SLC24A4 is associated with LOAD risk.134 Yu et al168 found pathology. Compared with control brains, PLD3 is expressed
the association of SLC24A4 with methylation, and brain at lower level in neurons from AD brains. Decreased expres-
DNA methylation has a role in the pathology of AD. RIN3 sion of PLD3 is associated with increase in extracellular
is located near SNP rs10498633 of SLC24A4. Interaction of Aβ42 and Aβ40.174
RIN3 and BIN1 plays an important role in endocytic path-
way.169 SLC24A4 is also involved in lipid metabolism.170 UNC5C
UNC5C gene is located on chromosome 4q22.3, and it is
DSG2 highly expressed in the adult hippocampus and cerebellum
DSG2 is located on chromosome 18q12.1, and it encodes neurons. Whole-genome sequencing and whole-exome
calcium binding transmembrane glycoprotein desmoglein. sequencing in European ancestry revealed the rare coding
Desmoglein-2 expression is abundant in epithelial cells and variant T835M (rs137875858) in netrin receptor UNC5C
cardiomyocytes. SNP rs8093731 at DSG2 reached genome- gene that showed significant association with LOAD.177
wide significance for LOAD in stage 1 but was not repli- A study by Wetzel-Smith et al177 revealed that neurons
cated in stage 2.38 Mutations in DSG2 have been associated with overexpression of T835M UNC5C are more prone to
with arrhythmogenic right ventricular cardiomyopathy and Aβ-mediated cell death, and T835M carriers with enhanced
sudden unexplained death.171 Alterations in the expression expression of UNC5C in the hippocampus are at increased
of desmogleins have been reported for a variety of cancers. risk of AD. In Chinese Han population, four rare variants
There is reduced expression of DSG2 in pancreatic cancer were detected near rs137875858, of which rs137875858
and overexpression of DSG2 in squamous cell carcinomas variant showed association with AD.178 Hunkapiller et al179
of the skin.172,173 showed that protein structure and death domain are affected
by overexpression of UNC5C variant T835M, and T835M
Novel sequencing technologies and carriers are more vulnerable to LOAD.
rare variants
GWASs successfully identified many common variants APP rare variant A673T
with low penetrance, not the rare variants associated with Jonsson et al25 performed whole-genome sequencing in
LOAD. However, advances in sequencing techniques such Icelandic population, and they found that a rare APP A673T

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substitution (rs63750847) confers protection against LOAD. are unable to explain a large proportion of the heritabil-
This variant was found to be more common in healthy elderly ity for LOAD. Linkage studies have not been effective in
controls than in AD and was associated with decreased cog- elucidating the genetic basis of LOAD due to small sample
nitive decline among elderly subjects without a diagnosis size and vulnerability to locus heterogeneity. Candidate
of AD, suggesting the protective role of rare APP A673T gene studies have not been successful in replicating genes
variant in LOAD.25 A673T variant reduces BACE1 cleavage consistently due to small sample size, locus heterogeneity,
of APP in primary neurons, resulting in decreased produc- and false-positive results. Due to poor understanding of roles
tion and aggregation of Aβ in A673T carrier.180 In contrast of encoded proteins, underlying biology, and effects of risk
to other Nordic populations, the A673T variant appears to be variants in AD pathogenesis, no therapeutic interventions
extremely rare in Danish and Asian population.181,182 have been developed to treat AD. Although mouse knockout
models have be used to study normal biology and the pathol-
AKAP9 ogy of AD, the AD field as a whole has struggled to develop
AKAP9 is located on chromosome 7q21-q22, and it encodes a drugs and potential novel targets from mouse models into
member of the AKAP family. AKAP9 is alternatively spliced effective therapies.
into many isoforms that localize to cellular compartments Recent studies have raised questions regarding the
such as centrosome and the Golgi apparatus. Logue et al183 validity of the amyloid hypothesis that has driven drug
conducted whole-exome sequencing in African American development strategies for AD for .20 years but has not
cases and identified two rare variants (rs144662445 and been unequivocally disproven, despite multiple clinical
rs149979685 within AKAP9) associated with AD. AKAP9 is failures.189,190 They concluded that the amyloid hypothesis
expressed in the hippocampus, cerebellum, and the cerebral may be failing therapeutically and suggest we expand our
cortex and interacts with numerous signaling proteins from view of pathogenesis beyond Aβ and tau pathology for the
multiple signal transduction pathways. Recently, Venkatesh understanding of AD pathogenesis.
et al184 found that deletion of AKAP9 in mice resulted in Experience from other complex diseases suggests that
marked alterations in the organization of microtubules affect- genes emerging from several studies require further valida-
ing blood–testis barrier function and subsequent germ cell tion via genetic replication and through functional assess-
development during spermatogenesis. Mutation in AKAP9 ment by in vitro and in vivo approaches to uncover common
was also associated with long QT syndrome-11 and congeni- genetic factors for AD. NGS can be used to detect rare and
tal long QT syndrome type 1 might be genetically modified structural variations in candidate regions. Novel approach can
by AKAP9.185 be developed to reassess the GWAS. Use of endophenotype
including cerebral spinal fluid biomarker data, quantitative
ADAM10 neuropathology measures, and phenotypes may be powerful
ADAM10 is located on chromosome 15q22, and it is ubiq- tools for the identification of genetic factors that influence
uitously expressed in a wide range of cell types, such as the AD risk and plausible biological pathways. Future research
neuroblastoma, kidney cell line, and the hepatocytes. Kim should be focused on identifying low effect size and rare
et al186 conducted genotyping and targeted sequencing in variants that may explain missing heritability. In future,
995 cases and 411 controls of European American origin deep resequencing can be used for an effective and accurate
and revealed that rare variant rs2305421 was associated with approach to identify novel rare variants associated with AD,
AD. However, Cai et al187 found that rare coding variation which might provide further insights into the underlying
in ADAM10 was not associated with sporadic AD. Suh mechanisms of disease. It is evident that epistatic interaction
et al188 found two rare mutations (Q170H and R181G) related is involved in complex diseases such as AD, and this should
to LOAD in ADAM10 and demonstrated that ADAM10 not be ignored. Furthermore, novel risk genes for AD can
mutations increased plaque load and Aβ levels and affect be identified by gene profiling. Additionally, missing AD
hippocampal neurogenesis in Tg2576 AD mice. heritability can be addressed with the development of more
sophisticated statistical analyses.
Challenges, controversies, and
future insights Conclusion
Despite years of research, much of the heritability of AD AD is a complex neurodegenerative disease with a strong
remains unexplained. Currently, most of the known genes genetic component. AD is a major public health problem, and

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Genes associated with Alzheimer’s disease:

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Table 1 Genes implicated in risk of early-onset Alzheimer’s disease

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Figure 1 Major pathways involved in AD and affected genes.

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Table 2 Common and rare variants associated with Alzheimer’s disease

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SORL1 of AD later in life.95 CR1 plays a key role in AD pathogenesis

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