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Duke University Medical Center

Department of Psychiatry and Behavioral Science

 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

Epidemiology of Dementia
Twins Study

Genetic Epidemiology of Alzheimer’s Disease in Twins, also known as Twins Study of Memory in Aging


 The Duke Twins Study of Memory in Aging investigates the genetic and non-genetic factors that influence how memory changes differ between the two members of a twin pair. 

The primary study is a population-based twin study of the occurrence of Alzheimer’s disease in the National Academy of Science – National Research Council (NAS-NRC) Twin Registry of World War II Veterans.  The purpose of this study is: 1) to investigate genetic causes of Alzheimer’s disease by comparing concordance for disease in identical and fraternal twin pairs, 2) to characterize and analyze the variability of onset of Alzheimer’s disease, while controlling for genetic factors, and  3) to search for specific environmental factors that may be associated with either accelerated or delayed onset of the disease. This study is funded by the National Institute on Aging. 

Links and Resources

Institute of Medicine Twins Registry

Institute of Medicine: 
Alzheimer's Disease in Twins Research Study

National Institute of Aging/National Institutes of Health

American Health Assistance Foundation
 



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 twin pairs. 

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. 



Bibliography

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 Disorders, 12:40-44.

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, 41:851-856.

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. Lancet, 345:387.

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..



For general information, please Contact Dept: 919-682-6722

For help with website: Roberta Moore at rmoore@psych.duhs.duke.edu
 


 
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