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Alzheimer's Disease in the National Academy of Sciences—National Research Council Registry of Aging Twin VeteransIII. Detection of Cases, Longitudinal Results, and Observations on Twin Concordance
John C. S. Breitner, MD, MPH;
Kathleen A. Welsh, PhD;
Barbara A. Gau, MSW;
William M. McDonald, MD;
David C. Steffens, MD;
Ann M. Saunders, PhD;
Kathryn M. Magruder, PhD;
Michael J. Helms, MS;
Brenda L. Plassman, PhD;
Marshal F. Folstein, MD;
Jason Brandt, PhD;
C. Dennis Robinette, PhD;
William F. Page, PhD
Arch Neurol. 1995;52(8):763-771.
Abstract
Objectives
To detect cases of Alzheimer's disease (AD) in a large population of twins living throughout the United States and to examine concordance for AD in twins as a function of age and genotype for apolipoprotein E (APOE).
Setting
Nationwide survey.
Design
Multistage screening and field evaluation beginning with two telephone interviews and culminating with laboratory tests, longitudinal neuropsychological measures, physician examination, and diagnostic consensus among experts.
Participants
Membership in 1990-1991 of intact pairs in the National Academy of Sciences—National Research Council Registry of veteran twins, then aged 62 to 73 years.
Main Outcome Measures
Completeness of case detection was examined in collateral studies. Zygosity and APOE genotypes were determined by restriction mapping. Concordance was calculated by the proband method.
Results
Ninety subjects who screened positively for AD were studied in person, and 60 whose differential diagnoses included AD were followed up, as were their cotwins. Sensitivity of screening was estimated at greater than 99%, but 24% of subjects refused participation after initial screening. Seven of 38 diagnoses of AD have been confirmed at autopsy, and 31 other subjects eventually met criteria for probable or possible AD (prevalence estimate, 0.42%; 95% confidence interval, 0.29% to 0.56%), with good interrater reliability (intraclass r=.86). Excluding one discordant pair with unknown zygosity, concordance rates were 21.1% (4/19) for monozygotic and 11.1% (2/18) for dizygotic probands. Concordance was 50% for twins sharing the  4/4 genotype at APOE, but there were no affected co-twins of 15 probands with onset before age 70 years, no 4 allele, and no family history of AD. The mean (SD) period of discordance in the latter pairs was 11.3 (3.3) years.
Conclusions
The multistage case-detection approach achieved reliable and valid diagnoses of AD with high apparent sensitivity but substantial attrition after initial screening. Genetic influences in AD at this age are limited, except among homozygotes for allele 4 at APOE. Subjects with early-onset AD who lack the 4 allele are not rare, and their condition appears to have little genetic influence. They should be ideal for studies on environmental causes of AD.
Author Affiliations
From the Department of Psychiatry (Drs Breitner, Welsh, McDonald, Steffens, and Plassman, Ms Gau, and Mr Helms), the Joseph and Kathleen Bryan Alzheimer's Disease Research Center (Drs Breitner, Welsh, Saunders, and Plassman), and the Center for the Study of Aging and Human Development (Dr Breitner), Duke University Medical Center, Durham, NC; Services Research Branch, National Institute on Mental Health, Rockville, Md (Dr Magruder); the Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Medical Institutions, Baltimore, Md (Dr Brandt); the Department of Psychiatry, Tufts-New England Medical Center, Boston, Mass (Dr Folstein); and the Medical Follow-Up Agency, Institute of Medicine, National Academy of Sciences, Washington, DC (Drs Robinette and Page).
Footnotes
Accepted for publication October 3, 1994.
This investigation was supported by grants AG-07922, AG-08549, and AG 05128 from the National Institutes of Health, Bethesda, Md; the Alzheimer's Association, Chicago, III; and the Sandoz Foundation for Gerontologic Research, Basel, Switzerland.
We gratefully acknowledge the expert advice of Marilyn Albert, PhD; James Anthony, PhD; Bernard Carroll, MD, PhD; Joe Christian, MD; Leonard Heston, MD; Albert Heyman, MD; Gerald McCleam, PhD; and James Mortimer, PhD. Merrill Benson, PhD, kindly performed DNA sequence analyses to screen for mutations in the amyloid precursor protein. Geraldine LaPlaca, MS, coordinated the clinical evaluations. Lena Leff MBA, Gail Atwater, Eric Bracey, Li Morrison, and Tiffany Newman assisted with management of the data. Christina Owens, RN, Judy Goodman, RN, Morda Messick, RN, Linda Jett, RN-C, Doreen Knedlik, RN, Valerie Royster, RN, and Lisad Millner, RN, performed the field assessments, assisted by psychometric technicians Sherri Strickland, Michelle Simons, Elise Goldwasser, and Hal Cockerham. Eric Friedrich, Stephen Leff, Jack Ruehsen, Nicole D'Andrea, and Phillip Baldwin assisted with the DQ interviewing. Ann Flaherty and Anne Johnson assisted with data entry. Kathi Rogers and Wilhelmina Westbrook assisted with project administration.
Reprint requests to Box 3925, Duke University Medical Center, Durham, NC 27710 (Dr Breitner).
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