Trajectories of blood-based biomarkers of AD, their determinants, and ability to predict cognitive impairment

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The AT(N) framework uses PET and/or CSF biomarkers to define Alzheimer’s Disease (AD) pathology and continuum; however, its broad implementation is restricted by high cost and limited accessibility. Recent advances in primarily Caucasian samples have identified plasma AD biomarkers – namely, the ratio of Aβ42/Aβ40 and phosphorylated tau (p-tau, e.g. p-tau181, p-tau217) – that are highly sensitive and specific for detecting abnormal Aβ and Tau. Plasma p- tau is particularly promising for AD diagnosis and prediction of conversion to AD; yet, their potential as markers of disease progression and risk predictors for mild cognitive impairment (MCI)/AD, especially among racial/ethnic minorities who are disproportionately affected by AD, remains largely unexplored. Here, our objective is to use trajectories of promising plasma AD biomarkers to 1) define their natural history, 2) their ability to predict the risk of developing AD- specific cognitive impairment, and 3) to identify their molecular determinants. We propose to measure Aβ42/Aβ40 and p-tau217 in 3,810 MESA participants, across five time points (Exam 1, 4, 5, 6 & 7) spanning 22 years, and human neuronal cell lines to achieve the following specific aims: Aim 1. To quantify two plasma AD biomarkers (p-tau217 and Aβ42/Aβ40) and determine their changes with age starting from age 45 to 100+. Aim 2. To determine the ability of baseline and longitudinal changes in plasma AD biomarkers to predict future cognitive impairment. Aim 3. To examine effects of vascular aging and cognitive decline-associated genomic features, that we have previously identified, on AD biomarkers. The proposed MESA longitudinal study combining plasma AD biomarkers with multi-omics data, cardiometabolic measures, brain imaging, cognitive testing, and clinical MCI/AD data across the mid- to late-life transition period is a critical next step to evaluate the utility of plasma AD biomarkers to predict future risk of cognitive impairment in a racially and ethnically diverse population, and to identify candidate causal molecular processes in early AD pathogenesis that could serve as targets for disease- modifying interventions.