ALZHEIMERS-DISEASE IN THE NATIONAL-ACADEMY-OF-SCIENCES NATIONAL RESEARCH COUNCIL REGISTRY OF AGING TWIN VETERANS .3. DETECTION OF CASES, LONGITUDINAL RESULTS, AND OBSERVATIONS ON TWIN CONCORDANCE

Objectives: To detect cases of Alzheimer's disease (AD) in a large pop ulation of twins living throughout the United States and to examine co ncordance for AD in twins as a function of age and genotype for apolip oprotein E (APOE). Setting: Nationwide survey. Design: Multistage scre ening and field evaluation beginning with two telephone interviews and culminating with laboratory tests, longitudinal neuropsychological me asures, 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 twi ns, then aged 62 to 73 years. Main Outcome Measures: Completeness of c ase detection was examined in collateral studies. Zygosity and APOE ge notypes were determined by restriction mapping. Concordance was calcul ated by the proband method. Results: Ninety subjects who screened posi tively for AD were studied in person, and 60 whose differential diagno ses included AD were followed up, as were their cotwins. Sensitivity o f screening was estimated at greater than 99%, but 24% of subjects ref used participation after initial screening. Seven of 38 diagnoses of A D 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 reliabilit y (intraclass r=.86). Excluding one discordant pair with unknown zygos ity, concordance rates were 21.1% (4/19) for monozygotic and 11.1% (2/ 18) for dizygotic probands. Concordance was 50% for twins sharing the epsilon 4/epsilon 4 genotype at APOE, but there were no affected co-tw ins of 15 probands with onset before age 70 years, no epsilon 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 cas e-detection approach achieved reliable and valid diagnoses of AD with high apparent sensitivity but substantial attrition after initial scre ening. Genetic influences in AD at this age are limited, except among homozygotes for allele epsilon 4 at APOE. Subjects with early-onset AD who lack the epsilon 4 allele are not rare, and their condition appea rs to have little genetic influence. They should be ideal for studies on environmental causes of AD.