Since 1976, the Framingham Heart Study (FHS) has surveilled participants for incident dementia, initially, in the Generation 1 participants, starting 1979 in the Generation 2 cohorts and in 1994 with the smaller multi-ethnic Omni Generation 1 cohort. As the oldest of the Generation 3 and Omni Generation 2 move into the age of dementia risk, we extended surveillance to these two younger cohorts. Baseline and repeat neuropsychological (NP) assessments and brain magnetic resonance imaging (MRI) scans have been conducted since 1999 on the Gen 1, Gen 2 and OmniGen 2 cohorts and since 2008 with the younger cohorts. Importantly, over nearly 7 decades, FHS has collected many co- morbid features linked to future risk of late life cognitive decline and dementia across these cohorts when they were early to middle age. Complementing the health and lifestyle data is the availability of genetic and peripheral biomarker data. Further, beginning in 2005, digital capture of spoken responses was added to NP testing. This was extended to written responses in 2011, allowing quantification of spoken and written responses at levels of granularity that can detect preclinical cognitive changes that traditional NP test scores cannot measure. Previously, we have capitalized on the multi-generation uniqueness using genome-wide approaches to discern novel genetic associations for AD risk and AD-related traits that were not identified in datasets up to 20 times larger. The primary goal of this FHS Brain Aging Program (FHS-BAP) is to continue dementia surveillance, extend longitudinal characterization of cognitive phenotypes and brain structure, bring added resources to the brain donation program including neuropathological examination, in the FHS cohorts in order to identify new and expand on known AD-related genetic and other risk factors and biomarkers and to pursue innovative research about the vascular and inflammatory basis of AD. Another central objective of FHS-BAP is to facilitate more widespread sharing of this extraordinary AD data resource with the broader scientific community. Under a new organizational structure, Administrative, Clinical, Neuropathology and Data cores will provide a formal management and infrastructure to continue incident dementia surveillance, NP and MRI assessments of surviving participants of all FHS cohorts, and perform neuropathological examination of brains obtained through the FHS brain donation program. The FHS-BAP will feature three inter-related projects that have a focus on vascular and inflammatory contributors to AD. One project will identify factors that are associated with AD risk and resilience using longitudinal analyses of FHS data including genetic, various `omic genetic, clinical, imaging, lifestyle and other traits. A second project will investigate the link between AD genetic vulnerabilities and chronic peripheral inflammation. A third project will determine genetic and protein alterations of complement-related genes and glial cell phenotypes that modulate cognitive trajectories and neuropathological profiles. Finally, this program will promote using FHS-BAP data, especially by early-stage and non-AD investigators through a pilot projects program and through enhanced and proactive data sharing efforts.
N AR R AT IVE The financial and societal cost of caring for 5.7 million people in the U.S. with Alzheimer disease (AD) is staggering and the suffering to those afflicted by AD and their families is incalculable. We expect that the Framingham Heart Study Brain Aging Program will improve our understanding of the roles of vascular and inflammatory factors in AD, identify new biomarkers for early diagnosis and prediction of disease course, determine circumstances that may lead to disease prevention and suggest potential novel therapeutic targets.