PRELIMINARY FINDINGS FROM AN ONGOING LONGITUDINAL METABOLOME-WIDE ASSOCIATION STUDY OF COGNITIVE DECLINE IN HEALTHY ADULTS WITH INCREASED RISK FOR ALZHEIMER’S DISEASE

Several cross sectional metabolomics studies of Alzheimer's disease (AD) have recently been reported, but a longitudinal examination of metabolomic profiles prior to AD diagnosis is crucial to establish early biomarker trajectories that influence the disease. Using longitudinal plasma samples from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort of participants who were asymptomatic at enrollment and enriched with a parental history of AD, metabolomic profiles are currently being quantified with mass spectrometry. This preliminary analysis is based on individuals with metabolomics data so far, which includes 28 participants with cognitive decline and 55 age- and gender-matched cognitively stable participants, each with up to 4 separate visits representing up to 6 years of follow-up. A metabolome-wide association study (MWAS) was performed using linear mixed effects regression models with the primary predictor being an interaction between age and cognitive status, indicating longitudinal change in metabolite levels by cognitive status. Findings were further tested for differences by clinical diagnosis using participants from the Wisconsin Alzheimer's Disease Research Center (W-ADRC), an independent cohort including 27 AD, 17 mild cognitive impairment (MCI), and 29 cognitively healthy participants with plasma metabolomics for 3 separate visits. Of the 615 metabolites tested in the WRAP cohort, 7 met a liberal statistical significance threshold (p