Current Directions in Psychological

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Genetics, Dementia, and the Elderly

Margaret Gatz
Current Directions in Psychological Science 2007 16: 123
DOI: 10.1111/j.1467-8721.2007.00488.x

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 CU R RE N T D I R E CT I O NS IN P SYC H OL OG I C AL SC I EN C E

Genetics, Dementia, and the

Elderly
Margaret Gatz

University of Southern California

ABSTRACT—Whether or not an individual develops de- He turned to his wife, ‘‘Rose, what was the name of that memory
mentia is powerfully influenced by genes. For Alzheimer’s clinic?’’ (Helpguide, 2005)
disease, the most common type of dementia, one suscepti-
bility gene with major effects has been identified, but A recent survey conducted by Harris Interactive for MetLife
progress finding other susceptibility genes has stalled. Twin Foundation found that, among Americans aged 55 and older,
studies have revealed that nongenetic risk also plays an Alzheimer’s disease (AD) was the most feared on a list of diseases
important role, as there are many monozygotic twin pairs (chosen by 31% of respondents, compared to 27% choosing
in which only one individual has dementia. Scientists have cancer and 20% choosing stroke; Harris Interactive, 2006). Fear
argued that gene-by-environment interactions will be key for one’s own cognitive future is especially strong among those
to understanding vulnerability to Alzheimer’s disease; but who watch their own parents develop dementia.
to date, few substantial gene-by-environment interactions Such a fear is not entirely misplaced. Among 65-year-olds,
have been replicated. Often, too, the nongenetic or lifestyle lifetime risk of developing any dementia has been estimated
factor appears to have a protective effect only for those to be 11% for men and 19% for women (Seshadri et al., 1997).
individuals not carrying the risky version of the gene, not Rates of dementia increase exponentially with age. The con-
for those individuals who are at genetic risk. sensus among expert scholars is that 30% of North Americans
aged 85 and older are living with dementia (Ferri et al., 2005).
KEYWORDS—dementia; Alzheimer’s disease; genetic risk;
Prevalence rates generally appear to be higher for African
twins
Americans than for Whites.
A number of investigators have addressed risk of AD in first-
Whether one’s future includes dementia is a concern for many degree relatives of AD patients, with estimates ranging from
middle-aged adults and, now, aging Baby Boomers. Ordinary 24% to 49%. In other words, lifetime risk of developing AD is 1.8
memory lapses have assumed the status of ‘‘senior moments.’’ to 4.0 times higher for those with a family history of the disorder
People play Sudoku as a form of mental exercise in the hopes that than for those without. Proportional increase in risk associated
it will stave off decline. Jokes about memory are traded by e-mail: with being a first-degree relative of an AD patient is similar for
African Americans and for Whites (Green et al., 2002). At the
same time, only a quarter of those with late-onset AD have had
Two elderly couples were enjoying friendly conversation when one
a close relative with dementia (Bird, 2005).
of the men asked the other, ‘‘Fred, how was the memory clinic you
went to last month?’’
‘‘Outstanding,’’ Fred replied. ‘‘They taught us all the latest psy- TYPES OF DEMENTIA
chological techniques: visualization, association, etc. It was great.’’
‘‘Sounds terrific! What was the name of the clinic?’’ Dementia refers to a group of diseases that have their onset in old
Fred went blank. He thought and thought, but couldn’t re- age and in which there is progressive loss of cognitive func-
member. tioning that eventually affects all aspects of self-care. Few
Then a smile broke across his face and he asked, ‘‘What do you dementias are reversible, although treatable factors that might
call that flower with the long stem and thorns?’’
contribute to cognitive decrements—for example, vitamin B12
‘‘You mean a rose?’’
‘‘Yes, that’s it!’’
deficiency, hypothyroidism, depression, or dehydration accom-
panying acute illnesses such as influenza—are important to
assess and address.
Address correspondence to Margaret Gatz, Department of Psychol-
ogy, University of Southern California, 3620 McClintock Avenue, Los The most common type of dementia is AD, accounting for up
Angeles CA 90089-1061; e-mail: gatz@usc.edu. to two thirds of all cases of dementia. The cause of AD is not

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 Genetics, Dementia, and the Elderly

established, although how it originates can be described. A key probandwise concordance. Probandwise concordance provides
feature is the formation in the brain of deposits of a protein called an indication of genetic risk. The magnitude of concordance
beta-amyloid (Ab); these deposits are called amyloid plaques. rates for MZ twin pairs and the difference in concordance be-
It is hypothesized that these plaques cause oxidative injury tween MZ and DZ twin pairs both suggest the extent of genetic
(damage due to release of free radicals during cellular metabo- influence. And when MZ concordance is less than 100%, it in-
lism), inflammation, and alterations in neurotransmitters, even- dicates that environmental influences or chance processes play
tually resulting in the death of neurons. AD is notable for a role.
its insidious onset. Clinically, impairment is typically observed We recently reported concordance rates for all dementia and
in episodic memory—due to either problems with learning or for AD in twins from the Swedish Twin Registry (Gatz et al.,
failures of retention. There are also deficits in language, visuo- 2006). These results are shown in Figure 1. Probandwise con-
spatial abilities, and executive function—with judgment and cordance for all dementias in men was 44% for MZ pairs and
problem solving often joining memory as the earliest reported 25% for DZ pairs, and in women it was 58% for MZ pairs and
symptoms. 45% for DZ pairs. However, concordance rates are influenced by
Other major types of dementia include dementia with Lewy length of life—and hence, opportunity to develop dementia.
bodies (DLB), vascular dementia (VaD), and frontotemporal de- Thus, although rates are higher for women than for men, once the
mentia. DLB is now considered the second most common form of age of the women was taken into account in quantitative genetic
dementia, accounting for 15 to 20% of all cases. The key feature models there was no significant difference in genetic influence
is aggregations of a protein called alpha-synuclein in subcortical by sex.
and cortical areas of the brain; these deposits are called Lewy Because dementia is age related, there is some chance that
bodies. Parkinsonism (e.g., slowness, muscular rigidity, tremor, any two older adults of equivalent age can both be expected to be
and impaired motor control) is observed in people with this form affected, independent of any shared genetic influences. From the
of dementia, along with falls, visual hallucinations, poor response same data, we created artificial pairs in which each individual
to antipsychotic medications, disturbed sleep, fluctuating at- was randomly coupled with an unrelated individual born in the
tention, and executive dysfunction (e.g., impaired judgment and same year. Converging results from thirty repetitions of this
problem solving). Autopsy results suggest that Lewy-related procedure are shown in Figure 1. Concordance was 12% and
pathology and AD-type pathology often occur together. 21% respectively for male and female unrelated pairs matched
VaD is characterized by cerebral infarcts (destruction of brain by birth year. The comparison of concordance rates for MZ twins,
tissue due to blockage of blood supply) or other evidence of DZ twins, and unrelated individuals highlights the influence of
cerebrovascular disease. VaD often has an abrupt onset and genetic factors for dementia vulnerability.
progresses in a stepwise fashion. Most notably, VaD is found to
impair executive functioning and psychomotor speed while
leaving episodic memory relatively intact. Estimated prevalence 100%
of this type of dementia depends greatly on which diagnostic
criteria are used. Autopsy studies suggest that prevalence of
80%
mixed AD with VaD is underestimated. With increased attention
Concordance Rate

to vascular risk factors for AD, there is also recognition of com-

mon mechanisms in how these two forms of dementia originate. 60%
Frontotemporal dementia entails loss of social awareness,
disinhibition, changes in eating habits, and changes in speech 40%
output, but not a pronounced memory deficit. Neuropathologi-
cally, there may be aggregations in the brain of a protein called
20%
tau. This type of dementia typically emerges at a younger age
than other dementias.
0%
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ESTIMATING GENETIC EFFECTS

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Twin studies are a useful tool in estimating the importance of

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genetic factors in the emergence of dementia. Monozygotic (MZ)

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twin pairs (i.e., who come from a single egg) are regarded as
being the same genetically. Dizygotic (DZ) twin pairs (i.e., from Fig. 1. Probandwise concordance rates for dementia (i.e., likelihood of
two eggs) share in principle half of their genetic makeup; ef- the partner being affected if one member of a pair has a disease), for
monozygotic twin pairs, dizygotic twin pairs, and unrelated pairs sharing
fectively, they are siblings of the same age. The proportion of the same year of birth, by sex. The number of pairs represented by the
twin partners of affected twins who also have a disorder is called columns are 428, 679, 1547, 655, 1009, and 1569, respectively.

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 Margaret Gatz

SPECIFIC GENES Genetic influences on AD are believed largely to stem from

predisposing rather than causative genes. The major suscepti-
A great deal of research attention has been devoted to identifying bility gene identified to date is the apolipoprotein E gene
the genes underlying dementia (summarized by Tsuang & Bird, (APOE). The ApoE protein is involved in the transport of cho-
2002). There are two kinds of genes—causative genes that follow lesterol during neuronal growth and after injury and in the de-
an autosomal dominant pattern of inheritance, and susceptibility position of Ab. The APOE gene has three versions or alleles—
genes. Autosomal dominant means that the risk to each child of e2, e3, and e4. Those who inherit an e4 allele from one parent
an affected parent is 50% and that inheriting one copy of the have greater risk of developing AD. There is a dose effect, with
mutation is sufficient to develop the disease. Susceptibility two e4 alleles being more unfavorable than one. Some studies
genes alter an individual’s chances of developing a disease or the find that the e2 allele is protective.
age at onset of a disease but are not in themselves sufficient to There is a higher occurrence of the e4 allele in African
cause the disease. Late-onset complex diseases such as AD are Americans than in Whites. However, surprisingly, most reports
rarely due to a single causative gene, and susceptibility genes find that APOE e4 is not a significant genetic risk factor for
account for more of the genetic risk than do causative genes. African Americans.
Three genes have been identified (see Table 1) in which par- Even including APOE, identified genes at best explain half of
ticular mutations cause AD following an autosomal dominant AD cases. It is estimated that there may be six or more additional
pattern of inheritance, typically with an early age of onset. Muta- susceptibility genes with major effects on risk of disease oc-
tions in these genes explain up to half of what is often called familial currence and age at onset (Bird, 2005). Susceptibility genes may
AD. However, because familial AD is so rare, these three estab- each add quantitatively to an individual’s personal risk. The
lished gene mutations account for under 2% of all cases of AD. more promising of these susceptibility genes are shown in

TABLE 1
Mutations and Susceptibility Genes Associated With Dementia, Their Locations, and Possible Pathways by Which Susceptibility Genes
Might Influence Risk of Alzheimer’s Disease (AD)

Gene Chromosome Possible pathway to AD susceptibility

AD mutations
Amyloid precursor protein gene (APP) 21 —
Presenilin 1 (PS1) 14 —
Presenilin 2 (PS2) 1 —

AD susceptibility genes
Apolipoprotein E (APOE) 19 Regulates beta-amyloid (Ab) deposition
a2-macroglobulin (a2M) 12 Plays a role in clearing Ab from the brain
Low density lipoprotein receptor-related protein 12 Serves as receptor for ApoE
(LRP)
Insulin degrading enzyme (IDE) 10 Regulates levels of insulin and degrades Ab
Angiotension I converting enzyme (ACE) 17 Plays a role in regulation of arterial blood
pressure and in Ab clearance
Interleukin 1 receptor alpha (IL-1a) 2 Regulates levels of proinflammatory protein
Adenosine triphosphate (ATP)-binding cassette 9 Mediates cellular cholesterol
transporter 1 (ABCA1)
Ubiquilin 1 (UBQLN1) 9 Regulates protein degradation
Sortilin-related receptor (SORL1) 11 Regulates generation of Ab

Dementia with Lewy Bodies mutations

a-synuclein 4 —

Vascular dementia mutations

Notch3 19 —

Fronto-temporal dementia mutations

Tau 17 —

Note. See Tsuang and Bird (2002) and Bertram, McQueen, Mullin, Blacker, and Tanzi (2007). The Bertram et al. article includes a meta-analysis and a link to the
AlzGene Web site (http://www.alzforum.org/res/com/gen/alzgene/default.asp), where complete results from all available studies of each susceptibility gene are
reported.

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 Genetics, Dementia, and the Elderly

Table 1. All of them relate to some aspect of how AD originates, association between depressive symptoms and cognitive decline
as described earlier in this paper, lending plausibility to how was found only for noncarriers of the risk alleles (Reynolds, Gatz,
each might contribute to increasing disease risk. A number of Berg, & Pedersen, in press).
these genes have been investigated with Swedish twin data— Thus, although individuals who have a positive family history
including, for example, the gene for insulin-degrading enzyme for AD are particularly interested in what steps they might be
(Prince et al., 2003). Research to date, however, is characterized able to take to reduce their chances of developing dementia, the
by many failures to replicate findings across studies. preponderance of findings suggests that lifestyle factors—such
For other types of dementia, some specific mutations, also as diet, ERT, physical exercise, and exposure to depression-
shown in Table 1, have been implicated, but only in rare forms evoking contexts—may be more important for those who are not
of these conditions. As for AD, there are familial cases not ex- at genetic risk than for those who are. People with a positive
plained by genetic discoveries to date. family history or who know that they are e4 carriers are still left
The question of genetic testing for dementia sometimes arises. with remarkably little reliable guidance about what might be
Genetic testing along with genetic counseling would be recom- protective.
mended in families in which one of the specific mutations is For vascular dementia, health habits related to preventing
suspected. But at present, potential misuses of testing for sus- stroke—e.g., avoiding smoking, obesity, and hypertension—are
ceptibility genes may outweigh the information gained. relevant to prevention. Further advances in understanding ge-
netic risk and potential gene-by-environment interactions are
GENE-BY-GENE AND GENE-BY-ENVIRONMENT likely to arise from identifying genes that make brain tissue more
INTERACTIONS or less susceptible to vascular injury.

Most scholars believe that dementia results from a combination

CONCLUSIONS AND FUTURE DIRECTIONS
of several genes acting together (gene-by-gene interactions) and
interactions between genes and multiple environmental factors
Taken together, twin studies and molecular-genetic studies in-
(gene-by-environment interactions). In testing for gene-by-en-
dicate that genetic factors are clearly important in dementia,
vironment interactions, the environment term encompasses
especially AD. A major new effort called the AD Genetics Ini-
anything to which an individual is exposed—hypertension or
tiative, funded by the National Institute on Aging, is being
education, for example—that might affect risk of dementia, al-
undertaken to identify these genes. Yet, equally evident is that
though clearly these factors might themselves be influenced by
genetic factors are only part of the picture, and finding the causes
other genes.
of dementia must entail more than a search for genes.
Gene-by-gene interactions have most often been examined by
Clinical trials and experimental studies, including animal
testing APOE e4 carrier status in concert with some other sus-
studies and neuroimaging work, will be useful complements to
ceptibility gene Findings have generally not shown consistent
epidemiological studies in obtaining evidence about the gene-
evidence of interaction. The ability to find reliable results and to
by-environment interactions. Future research might also build
test complex interactions among multiple genes should become
on twin studies—for example, focusing on MZ pairs who share
possible with larger databases and more sophisticated analytic
particular susceptibility genes but in which only one of the pair
approaches (Bertram, McQueen, Mullin, Blacker, & Tanzi,
has dementia.
2007).
Finally, epigenetic phenomena may play a key role in ex-
Finding gene-by-environment interactions has proved elu-
plaining dementia. Epigenetic differences refer to changes in
sive. Where there have been significant results, they have not
genetic material that arise during development. These could be
always been intuitive. In African American participants from the
seen as chance events during DNA replication that do not alter
Indianapolis-Ibadan Dementia Project, for example, lower total
the DNA sequence but change whether a particular gene is ac-
serum cholesterol was related to reduced risk of AD only in those
tive or not. Twin studies are an important tool because identical
who carried no e4 alleles (Evans et al., 2000). In Cardiovascular
twins can accumulate differences between them due to epige-
Health Study participants, it was found that estrogen replace-
netic modifications (Wong, Gottesman, & Petronis, 2005). Dis-
ment therapy (ERT) was related to lower risk of becoming cog-
cordance for dementia among monozygotic twin pairs could
nitively impaired, but only among women who carried no e4
be explained by epigenetic differences arising by chance, differ-
alleles (Yaffe, Haan, Byers, Tangen, & Kuller, 2000), and that
ences in environmental influences, or environmental factors that
physical exercise was significantly associated with reduced risk
have a long-term influence on epigenetic modifications.
of subsequently developing dementia, but, again, only among e4
noncarriers (Podewils et al., 2005). In analyses of MZ twins from
Sweden, intrapair differences in depressive symptoms were Recommended Reading
associated with intrapair differences in cognitive decline. How- Cummings, J.L., & Cole, G. (2002). Alzheimer disease. JAMA: The
ever, for both estrogen receptor alpha (ESR1) and APOE, the Journal of the American Medical Association, 287, 2335–2338.

126 Downloaded from cdp.sagepub.com at OAKLAND UNIV on May 4, 2013 Volume 16—Number 3
 Margaret Gatz

Gatz, M., & Brommelhoff, J. (in press). The implications of genetic explaining Alzheimer’s disease. Archives of General Psychiatry, 63,
testing for Alzheimer’s disease in an aging society. In C.Y. Read, 168–174.
R.C. Green, & M.A. Smyer (Eds.), Aging, Biotechnology, & the Green, R.C., Cupples, L.A., Go, R., Benke, K.S., Edeki, T., Griffith,
Future. Baltimore: Johns Hopkins University Press. P.A., et al. (2002). Risk of dementia among White and African
Gatz, M., Prescott, C.A., & Pedersen, N.L. (2006). Lifestyle risk and American relatives of patients with Alzheimer disease. JAMA: The
delaying factors. Alzheimer Disease & Associated Disorders, Journal of the American Medical Association, 287, 329–336.
20(Suppl. 2), S84–S88. Harris Interactive. (2006, May 11). MetLife Foundation Alzheimer’s
Read, C.Y., Roberts, J.S., Linnenbringer, E., & Green, R.C. (in press). survey: What America thinks. Retrieved June 30, 2006, from
Genetic testing for Alzheimer’s disease: The REVEAL Study. In http://www.metlife.com/WPSAssets/20538296421147208330V1F
C.Y. Read, R.C. Green, & M.A. Smyer (Eds.), Aging, Biotechnol- AlzheimersSurvey.pdf
ogy, & the Future. Baltimore: Johns Hopkins University Press. Helpguide. (2005, October). Jokes to make you laugh. Retrieved July 2,
2006, from http://www.helpguide.org/life/jokes/oct_05.htm
Podewils, L.J., Guallar, E., Kuller, L.H., Fried, L.P., Lopez, O.L.,
Carlson, M., & Lyketsos, C.G. (2005). Physical activity, APOE
Acknowledgments—Research described in this article was genotype, and dementia risk: Findings from the Cardiovascular
supported in part by National Institute on Aging Grant Health Cognition Study. American Journal of Epidemiology, 161,
R01AG08724. I am grateful for comments by Malcolm Klein, 639–651.
Prince, J.A., Feuk, L., Gu, H.F., Johansson, B., Gatz, M., Blennow, K., &
Chandra Reynolds, and Martha Storandt.
Brookes, A.J. (2003). Genetic variation in a haplotype block
spanning IDE influences Alzheimer disease. Human Mutation,
REFERENCES 22, 363–371.
Reynolds, C.A., Gatz, M., Berg, S., & Pedersen, N.L. (in press). Ge-
Bertram, L., McQueen, M.B., Mullin, K., Blacker, D., & Tanzi, R.E. notype–environment interactions: Cognitive aging and social
(2007). Systematic meta-analyses of Alzheimer disease genetic factors. Twin Research and Human Genetics.
association studies: The AlzGene database. Nature Genetics, 39, Seshadri, S., Wolf, P.A., Beiser, A., Au, R., McNulty, K., White, R., &
17–23. D’Agostino, R.B. (1997). Lifetime risk of dementia and Alzhei-
Bird, T.D. (2005). Genetic factors in Alzheimer’s disease. New England mer’s disease. The impact of mortality on risk estimates in the
Journal of Medicine. 352, 862–864. Framingham Study. Neurology, 49, 1498–1504.
Evans, R.M., Emsley, C.L., Gao, S., Sahota, A., Hall, K.S., Farlow, M.R., Tsuang, D.W., & Bird, T.D. (2002). Genetics of dementia. Medical
& Hendrie, H. (2000). Serum cholesterol, APOE genotype, and the Clinics of North America, 86, 591–614.
risk of Alzheimer’s disease: A population-based study of African Wong, A.H., Gottesman, I.I., & Petronis, A. (2005). Phenotypic
Americans. Neurology, 54, 240–242. differences in genetically identical organisms: The epigenetic
Ferri, C.P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, perspective. Human Molecular Genetics, 14(Supp. 1), R11–
M., et al. (2005). Global prevalence of dementia: A Delphi con- R18.
sensus study. Lancet, 366, 2112–2117. Yaffe, K., Haan, M., Byers, A., Tangen, C., & Kuller, L. (2000). Estrogen
Gatz. M., Reynolds, C.A, Fratiglioni, L., Johansson, B., Mortimer, J.A., use, APOE, and cognitive decline: Evidence of gene–environment
Berg, S., et al. (2006). The role of genes and environments for interaction. Neurology, 54, 1949–1954.

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