DESCRIPTION (provided by principal investigator): It is increasingly recognized that although clinical manifestations of many neurological disorders occur in later decades, an individual's susceptibility to disease is determined early in life. In the Framingham Heart Study, we have identified genetic, cardiovascular risk factor and biomarker data related to the subsequent development of AD in our Original Gen1, elderly cohort that are also associated with structural and cognitive endophenotypes (heritable intermediate phenotypes) in our Offspring Gen2, middle aged cohort. In the proposed MRI, Genetic, Cognitive & Biomarker Precursors of AD & Dementia in Young Adults grant we hypothesize that the structural and cognitive continuum we have observed in our younger Gen2 participants represents the lengthening of a continuum that begins even earlier in life and will be extended to this still younger Gen3 cohort. Gen 3 represents a richly characterized group of young-adults in whom dense genotyping, comprehensive biomarker and abundant vascular risk factor, documented family occurrence of disease such as AD and dementia, and subclinical atherosclerosis data are available. Our primary goal is to characterize brain morphology on MRI and cognitive function in the Gen3 cohort, specifically previously identified endophenotypes of AD and dementia (such as total and regional brain volumes, white matter lesions, and regional quantitative measures of the hippocampal and entorhinal cortex as well as memory and executive function.) We predict within this younger Gen3 cohort there is an identifiable continuum of structural and cognitive indices linked to dementia and brain aging. We will also relate previously measured vascular, metabolic, inflammatory, family occurrence of AD/dementia and other risk factor data already available on these subjects to the range of structural and functional AD/dementia endophenotypes. We posit that a subset of the risk factors previously identified in the older Gen2 cohort will show similar associations in Gen 3. Further we anticipate uncovering additional risk factors related to AD/dementia endophenotypes unique to this younger cohort. Finally, we will utilize the extensive genetic resources currently available in all three generations of the Framingham cohorts to uncover age-specific genetic effects, gene environment interactions and novel genetic relationships. This application represents a resource-effective mechanism to leverage the wealth of genetic, risk factor and biomarker data collected in this younger adult community-based population to greatly enrich our understanding of preclinical AD and pathophysiology of disease.