Proteomic aging clock and brain structure, cognitive decline and the risk of Alzheimers Disease and related dementias

PROJECT SUMMARY To assess biological aging before clinical diagnosis of Alzheimer’s Disease (AD) and Alzheimer's-disease- related dementias (ADRD), we will create and validate proteomic aging clocks (PACs) in the prospective population-based Atherosclerosis Risk in the Community (ARIC) cohort. The blood proteomics measures have been collected three times over 20 years of follow-up using highly sensitive SomaScan assay. PACs are easily measured, can accurately predict the aging process, and are associated with age-related diseases and mortality. Our main objectives are to create and validate PACs in AD/ADRD-free participants and test whether these PACs predict risk of ADRD, cognitive decline and structural abnormalities visible in brain imaging such as parenchymal loss, white matter hyperintensities, and small infarcts. We will assess two published PACs and create two new PACs: (1) PAC based on the association with chronological age in AD/ADRD-free persons of mixed age, and (2) PAC based on the change in protein levels between midlife and late-life (Aim 1). Further, we will test whether higher PAC value (independent of chronological age) and higher intra-individual difference in the PAC values from midlife to late-life are associated with higher risk of AD/ADRD (Aim 2), and with decline in cognitive function and with structural abnormalities visible in brain imaging in late-life (Aim 3). All the associations will be stratified by sex and race. The use of existing ARIC data will allow for quick and cost- efficient testing of our hypotheses. The quantification of PAC and clarification of its relations with AD/ADRD are essential for understanding the role of aging in the pathobiology of this disease, identifying individuals at high risk, and efficiently delivering personalized prevention/treatment via lifestyle change and anti-aging therapies.