In this Program Project we plan to expand the evidence indicating that life span is strongly inherited in families with exceptional longevity. Avoiding age-related and dementia-related cognitive decline are essential to successful aging. Our studies of centenarians and their offspring (LonGenity) have lead to the identification of a number of longevity genes and corresponding phenotypes. At cross-section, we have shown that some of these genotypes (e.g., cholesterol ester transfer protein, ApOCS and adiponectin) and phenotypes (e.g., HDL level, lipoprotein particle size distribution, adiponectin level) are also associated with preservation of cognitive function. Herein, we propose to expand and follow a cohort of offspring of parents with exceptional longevity (OPEL, n=600) as well as a control sample of offspring of parents with usual survival (OPUS, n=600). Both groups will be followed with annual in-person clinical and neuropsychological assessments to identify incident amnestic Mild Cognitive Impairment and dementia. This project will allows us to assess the contribution of three levels of exposure variables (exceptional parental longevity, longevity genotypes and longevity phenotypes) on two levels of cognitive outcomevariables. The outcomes of interest here are cognitive decline in the domains of memory and executive function as well as amnestic Mild Cognitive Impairment (aMCI) and dementia. We hypothesize that offspring of probands with exceptional longevity have a reduced rate of cognitive decline and a reduced incidence of dementia and aMCI and that favorable cognitive outcomes are associated with specific longevity genotypes and phenotypes. The Clinical Core will collect the data and information will be made available through the Statistics and Data Management Core and its Bioinformatics Sharing facility. The correlation between CVD and its risks with cognitive decline will assess through interaction with project 3. Newly discovered genes in projects 1&2 will be made available for testing cognitive hypotheses in this longitudinal study.