Multi-ancestry studies in multi-omics of Alzheimer's disease: Recent insights and future directions

The past decade of multi-omics studies revealed perturbations in genetic, epigenetic, transcriptomic, proteomic, and metabolic networks in Alzheimer's disease (AD) detected in brain, cerebrospinal fluid (CSF), and blood biospecimens. Interactions among these networks and environmental factors are thought to contribute to risk and progression of this neurodegenerative dementia. Understanding the molecular and environmental risk in AD across all populations is essential in the development of cures and biomarkers for this complex disease. While most molecular studies to date have focused on populations of European ancestry, emerging multi-ancestry and multi-omics studies are revealing both shared and ancestry-specific biological signatures associated with disease susceptibility, biomarker profiles, and clinical presentation. Genomic studies show that established AD risk loci such as APOE, ABCA7, and TREM2 exhibit ancestry-dependent effects, while trans-ethnic genome-wide association studies identified novel disease risk loci (e.g., LRRC4C, LHX5-AS1) and protective haplotypes unique to African American (AA) and admixed populations. Epigenomic and transcriptomic studies reveal ancestry-linked variation in chromatin accessibility, DNA methylation, and gene expression, particularly in immune, lipid metabolism, and synaptic pathways. Proteomic analyses demonstrate differences in CSF and brain protein networks, including extracellular matrix and synaptic modules enriched or reduced in AA AD brains. Metabolomic and lipidomic data further highlight differential abundance in non-European cohorts. Integrating these multi-omics layers across ancestries provides a framework for understanding how genetic background and environmental context interact to drive AD heterogeneity. Such integrative, ancestry-aware approaches will refine biomarker interpretation, improve diagnostic accuracy, and guide development of therapeutics for AD.