Duke University Twins Study of Memory in Aging
The Duke Twins Study of Memory in Aging conducts research on the genetic
and non-genetic causes of dementia, particularly Alzheimer's disease.
The program began in 1989 and has primarily focused on the study of twin
pairs in which one or both twins have Alzheimer's disease. The participants
in the studies have come from two sources. The first source is the
National Academy of Science - National Research Council (NAS-NRC) Registry
of Male World War II Veterans. This part of the study is funded by
the National Institutes on Aging. In 1990, this Twin Registry consisted
of over 7000 twin pairs living throughout the continental U.S. As
of late 2005, we have identified about 334 cases of Alzheimer's disease
in this Registry. The second source of twins are individuals who
have volunteered to participate in response to advertisements about our
study in various Alzheimer's disease newsletters. The research on
this latter group has been partially funded by the American Health Assistance
Foundation (AHAF). To date, this latter group consists of about 125
A little background of what we know about the genetic (hereditary) causes
of Alzheimer's disease might be helpful here. To date, four genes
have been identified (and confirmed repeatedly) that cause or increase
the risk of Alzheimer's disease. Three of these genes appear to be
autosomal dominant which means virtually everyone who has the gene will
develop Alzheimer's disease and these individuals are often said to have
familial Alzheimer's disease. Mutations on these three genes generally
cause the onset of the disease before age 65, which is often termed early
onset Alzheimer's disease. However, these familial cases probably
account for less than 5% of all Alzheimer's disease cases. The fourth
gene identified is the apolipoprotein E (APOE) gene. The APOE gene
has three common alleles, of which the e4 allele appears to predispose
(increase the risk) at least some individuals to getting the disease or
getting the disease earlier. This means that only some individuals
who have this gene will get Alzheimer's disease. This gene appears
to play a role in many more cases of Alzheimer's disease (particularly
those with onset after age 60) than the other autosomal dominant genes
noted above. However, it does not account for all of the remaining cases
of the disease that appear to be genetic. The fact that there are
many families with numerous members with Alzheimer's disease, who do not
have any of the risk genes identified to date, indicates that other genes,
yet unidentified, play a role in the disease. In addition, it is
also not known why some individuals with the APOE 4 allele get Alzheimer's
disease and some do not, but clearly some other genetic or non-genetic
factors must also play a role in determining which of these individuals
get the disease.
Twin studies can make a major contribution in identifying these
non-genetic factors. Twin studies have shown that if one member of
a twin pair gets Alzheimer's disease, the other twin is at increased risk
of getting the disease, but often the other twin does not get the disease
or s/he gets the disease much later. So how do twin studies help
us understand the causes of Alzheimer's disease. Our studies
use the twin method to try to identify non-genetic (environmental) factors
that might increase or decrease the risk of getting Alzheimer's disease.
The twin method is based on the premise that identical twins (monozygotic
twins) share 100% of their genes and fraternal (dizygotic twins) share
on average 50% of their genes. Higher concordance rates for Alzheimer's
disease (i.e. both members of the twin pair have the disease) in identical
twin pairs compared to fraternal twin pairs provides evidence for genes
playing a role in the disease. However, if the disease was solely
due to genes, then if one member of an identical twin pair got the disease,
the other twin would get it 100% of the time. Studies have shown that this
is not the case. Although the estimates of concordance within twin pairs
vary based on age of the twins and the specific study, one could reasonably
estimate that about 50% of the time if one twin gets Alzheimer's disease
the other twin will get the disease.
Within identical twin pairs, the differences in the tendency for the
second twin in a pair to get the disease must be attributable to non-genetic
factors. These non-genetic factors may act in different ways.
Some factors may delay or prevent the disease, while others may increase
the risk of disease. For example, these factors may cause one twin
to get the disease while the other twin never gets the disease; or a given
factor may cause one twin to get the disease much earlier or later than
the other twin. Twin studies can also be used to study the
interaction between non-genetic factors and specific genes that have been
shown to modify the risk of Alzheimer's disease. For example, if
we know Gene A increases the risk of Alzheimer's disease in some individuals
but not everyone who has Gene A gets the disease, then we can see if those
individuals with Gene A only get the disease if they are exposed to environmental
Factor B. These non-genetic or environmental factors may include
occupational exposures, medical illnesses, and medications.
Twin studies can also provide other important information about the
genetic and non-genetic causes of Alzheimer's disease. Information
about both identical and fraternal twin pairs can be used in complex analyses
to estimate the extent to which genetic and non-genetic factors contribute
to Alzheimer's disease. For example, say we study 50 identical twin
pairs and 50 fraternal twin pairs in which every pair has at least one
twin with Alzheimer's disease. If in 35 of the identical twin pairs
both members have Alzheimer's disease (i.e. are concordant for Alzheimer's
disease) and in only 20 of the fraternal pairs both members have the disease,
then we know that genes play a role in the cause of the disease.
We can then use analytical methods to estimate: 1) how much genes contribute
to the disease, 2) how much unique non-genetic exposures contribute (meaning
one twin was exposed to a given factor and one was not), or 3) shared non-genetic
exposures (meaning both twins were exposed to a given factor). Because
(as stated above) not all of the genes which contribute to Alzheimer's
disease have been identified, twin studies provide the only means of estimating
how much of the cause of the disease is due to genes and how much is due
to environmental factors.
These types of analyses require large numbers of twin pairs. Thus,
we will still be collecting information on some of the twin pairs over
the next few years and analyses will be ongoing for some time. To
date, in the NAS-NRC Twin Registry, of those twin pairs in which at least
one member has Alzheimer's disease, only about 40% of the identical twin
pairs are concordant for the disease and about 20% of the fraternal twin
pairs are concordant for the disease. In some twin pairs, the one
twin remains unaffected (i.e. does not have the disease) even 19 years
after the onset of Alzheimer's disease in the other twin. We
suspect that the concordance rate in our twin pairs will increase as the
Registry members get older.
1) Plassman, B.L., Khachaturian, A.S., Townsend, J.J., Ball, M.J., Steffens,
D.C., Leslie, C.E., Tschanz, J.T., Norton, M.C., Burke, J.R., Welsh-Bohmer,
K.A., Hulette, C.M., Nixon, R.R., Tyrey, M., Breitner, J.C.S. (2006) Comparison
of clinical and neuropathological diagnoses of AD in three epidemiological
samples. Alzheimer’s and Dementia. 2:2-11.
2) Steffens, D.C., Maytan, M, Helms, M.J., Plassman, B.L. (2005)
Prevalence and clinical correlates of neuropsychiatric symptoms in dementia.
American Journal of Alzheimer’s Disease. 20:367-373.
3) Reed, T., Plassman, B.L., Tanner, C.M., Dick, D.M., Rinehart, S.A.,
Nichols, W.C. (2005) Verification of self-report of zygosity determined
via DNA testing in a subset of the NAS-NRC Twin Registry 40 years later.
Twin Research and Human Genetics. 8:362-367.
4) Potter, G.G., Plassman, B.L., Helms, M.J., Steffens, D.C. and Welsh-Bohmer,
K.A. (2004) Age effects of coronary artery bypass graft on cognitive status
change among elderly male twins. Neurology. 63:2245-2249.
5) Gurland, B.J., Page W.F., Plassman, B.L. (2004) A Twin Study of the
Genetic Contribution to Age-Related Functional Impairment. Journal
of Gerontology: Medical Sciences. 59:M859-M863.
6) Steffens, D.C., Plassman, B.L., Helms, M.J., Welsh-Bohmer, K.A.,
Newman, T.T., Breitner, J.C.S. (2000). Apolipoprotein E genotype,
concordance and discordance of Alzheimer’s disease (AD) in twin pairs as
predictors of AD in first-degree relatives. Neurology. 54:593-598.
7) Breitner, J.C.S., Jarvik, G.P., Plassman, B.L., Saunders, A.M., Welsh-Bohmer,
K.A. (1998). Risk of Alzheimer’s disease with the ?4 allele for apolipoprotein
E in a population of men aged 62-73. Alzheimer Disease and Associated
8) Plassman, B.L., Welsh-Bohmer, K.A., Bigler, E.D., Johnson, S.C.,
Anderson, C.V., Helms, M.J., Saunders, A.M., Breitner, J.C.S. (1997). Apolipoprotein
E ?4 and hippocampal volume in twins normal cognition. Neurology, 48:985-989.
9) Steffens, D.C., Plassman, B.L., Helms, M.J., Welsh-Bohmer, K.A.,
Saunders, A.M., Breitner, J.C.S. (1997). A twin study of late-onset depression
and apolipoprotein E ?4 as risk factors for dementia. Biological Psychiatry,
10) Plassman, B.L., Welsh, K.A., Breitner, J.C.S., Brandt, J., Helms,
M., Page, W.F. (1995). Intelligence and education as predictors of cognitive
state in late life: A 50 year follow-up. Neurology, 45:1446-1450.
11) Breitner, J.C.S., Welsh, K.A., Gau, B.A., McDonald, W.M., Steffens,
D.C., Saunders, A.M., Magruder, K.M., Helms, M.J., Plassman, B.L. Folstein,
M.F., Brandt ,J., Robinette, C.D., Page, W.F. (1995). Alzheimer's disease
in the National Academy of Sciences-National Research Council Registry
of Aging Twin Veterans. III. Detection of cases, longitudinal results,
and observations on twin concordance. Archives of Neurology, 52:763-771.
12) Plassman, B.L., Saunders, A.M., Helms, M.J., Breitner, J.C.S.,
Welsh, K.A. (1995). Smoking, Alzheimer's disease, and confounding with
genes - authors reply. Lancet, 345:1054.
13) Plassman, B.L., Helms, M.J., Welsh, K.A., Saunders, A.M., Breitner,
J.C.S. (1995). Smoking, Alzheimer's disease, and confounding with genes.
14) Plassman, B.L., Newman, T.N., Welsh, K.A., Helms, M., Breitner,
J.C.S. (1994). Properties of the Telephone Interview for Cognitive Status:
Application in epidemiological and longitudinal studies. Neuropsychiatry,
Neuropsychology, and Behavioral Neurology, 7:235-241.
15) Breitner, J.C.S., Gau, B.A., Welsh, K.A., Plassman, B.L.,
McDonald, W.M., Helms, M.J., Anthony, J.C. (1994). Inverse association
of anti-inflammatory treatments and Alzheimer's disease. Neurology, 44:227-232..
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