DESCRIPTION: (Abstract from application) For this exploratory proposal, we will develop the hypothesis that active survival into old age is highly dependent on the preservation of cognitive and physical function, and that the preservation of these functions is, in part, inherited. We will use longitudinal data from two cohorts of elderly African-Americans, Caribbean Hispanics and whites in northern Manhattan and their families to identify potential candidate phenotype definitions for genetic analysis. The phenotypes of interest will be related to the rate-of-change with age in cognitive and physical function, and to the age at which individuals reach critical stages in these functional domains. First, previously collected longitudinal data will be used to determine the rate-of-change with age in specific measures of cognitive performance and physical function, develop specific indicators of clinically meaningful changes corresponding to the loss of ability and determine the age-at-onset of these changes within strata defined by ethnic group, major disease categories, lifestyle factors and specific allelic polymorphisms. Interactions between genotypes and disease and lifestyle factors will be explored for their combined effects on the rate-of-change and the age-at-onset of specified changes in cognitive or physical function. Shared genetic effects on the phenotypic measures and years of total and active survival will be investigated in these individuals and their first-degree family members. In a recently established cohort we will recruit their same-sex siblings to analyze concordance in cognitive and physical function, concordance in rate-of-change in these functions based on retrospective interviews and familial aggregation of time-to-event measures in probands and first-degree relatives. We will collect and store DNA from examined siblings for future linkage or association studies, and we will assess the feasibility of repeated examinations in the siblings, in terms of participation and attrition rates, loss to follow-up, location of examinations, clinical procedures to be included, etc. We will use the experience in this multi-ethnic community to obtain information about phenotype definitions, study designs, sample size requirements, and analytic tools to detecting genes influencing the rate-of-change in cognitive and physical function.