Abstract
Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), with numerous studies characterizing metabolic pathways associated with AD onset and progression. A significant limitation of these studies has been a predominant focus on non-Hispanic white participants. Despite evidence that AD prevalence, progression, and biomarkers differ across ethnoracial groups, it remains unclear whether previously identified metabolic dysregulation in AD brains generalizes across populations. We addressed this gap by analyzing large-scale metabolomics data from 547 postmortem dorsolateral prefrontal cortex brain tissue samples of Hispanic American, Non-Hispanic African American, and White subjects, providing the largest multiethnic AD brain cohort analyzed to date. A metabolome-wide association study examined how relationships between metabolite abundance and AD neuropathology varied by ethnoracial group. Sixty metabolites exhibited significant heterogeneity with tau pathology (Braak stage), with enrichment in tricarboxylic-acid-cycle intermediates, dipeptides, and sphingolipid-ceramide pathway lipids. These findings reveal ethnoracial-specific metabolic signatures of tau pathology and emphasize the need to evaluate emerging therapeutic targets across diverse groups.