Sphingolipid and ceramide associations with tau pathology vary across diverse ethnoracial groups in postmortem brain tissue.

INTRODUCTION

Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), with numerous studies characterizing metabolic pathways associated with AD onset and progression. A limitation of these studies has been a 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.

METHODS

We analyzed metabolomics data from 547 postmortem brain tissue samples of Hispanic American, Non-Hispanic African American, and White subjects, providing the largest multiethnic AD brain cohort to date. A metabolome-wide association study examined how relationships between metabolite abundance and AD neuropathology varied by ethnoracial group.

RESULTS

Forty-eight metabolites exhibited significant heterogeneity with tau pathology (Braak stage), with enrichment in tricarboxylic-acid-cycle intermediates and sphingolipid-ceramide pathway lipids, and with metabolite-tau associations driven predominantly by the Hispanic American and non-Hispanic White groups.

DISCUSSION: These findings reveal ethnoracial-specific metabolic signatures of tau pathology and emphasize the need to evaluate emerging therapeutic targets across diverse groups.