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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 co-twins. 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 epsilon 4/epsilon 4 genotype at APOE, but there were no affected co-twins 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 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 epsilon 4 at APOE. Subjects with early-onset AD who lack the epsilon 4 allele are not rare, and their condition appears to have little genetic influence. They should be ideal for studies on environmental cause of AD.

Objective: To assess interrater reliability and validity of NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) criteria for Alzheimer's disease (AD)., Design: A multisite reliability and validity study in which clinicians from each site diagnosed 60 case summaries yielding a preconsensus estimate of reliability and validity. A consensus conference was conducted for each disagreement, leading to a postconsensus estimate of validity. The criterion standard was a diagnosis of AD by autopsy., Setting: Three academic medical centers., Subjects: A convenience sample of 60 detailed case summaries, 40 with AD and 20 with other dementing disorders., Main Outcome Measures: The kappa coefficient, sensitivity, and specificity., Results: The kappa coefficient for preconsensus agreement on a diagnosis of probable or possible AD vs non-AD was 0.51; the sensitivity of a diagnosis of probable or possible AD for a pathological diagnosis of AD was 0.81, and the specificity was 0.73. The postconsensus sensitivity was 0.83, and the specificity was 0.84., Conclusions: The results support the reliability and validity of NINCDS-ADRDA criteria and show that the consensus process may improve diagnostic accuracy. The cases are reviewed with a focus on the sources of diagnostic disagreements and errors and possible changes that might improve the accuracy of the criteria.

Objective: To determine the contribution of genetic factors to cognitive functioning in older men., Design: Cognitive testing by telephone interview in an epidemiologically defined population., Participants: 2077 monozygotic and 2225 dizygotic male twin pairs, all between the ages of 62 and 73 years, recruited from the National Academy of Sciences twin registry., Main Outcome Measures: The Telephone Interview for Cognitive Status--Modified total score and factor scores were analyzed. The Falconer heritability statistic and maximum likelihood estimates of genetic and environmental components were computed., Results: Heritability of the total Telephone Interview for Cognitive Status--Modified score was estimated to be 30%. Shared environmental effects accounted for an additional 18% of the variance; most of this was related to years of education. Of the four cognitive factors derived, the language/attention factor had the highest heritability estimate., Conclusions: Genetic factors and educational achievement together account for almost half of the variance in the cognitive functioning of older men. Studies of the genetics of dementing illnesses need to consider the degree to which cognitive capacities are themselves under genetic control.

To determine how accurately dementia was diagnosed among medical inpatients, we compared the judgments of medical interns with diagnoses based on standard criteria. Fifty-seven interns rendered opinions regarding the presence of dementia in 380 medical inpatients who were simultaneously examined by physician-investigators applying criteria derived from DSM III. The sensitivity and specificity of diagnosis by interns were 79% and 80%, respectively. Patients who were misdiagnosed as demented were less likely to be high school graduates than their correctly classified nondemented counterparts, and those with unrecognized dementia were more likely to be younger than 65 years than patients whose dementia was recognized by house staff. It is concluded that misdiagnosis is related to age and educational status and that attention to these factors may improve diagnostic accuracy.