Analyses of plasma multi-omic data across ancestries identify novel pathways implicated in Alzheimer's disease

Few genetic studies on Alzheimer's disease (AD) have incorporated multiple ancestries and omic datasets to pinpoint actionable AD risk effectors for each ancestry.

Here, we first performed genetic colocalization between molecular phenotypes (proteomics and metabolomics) from two ancestral groups (European [EUR] and African [AFR]) and the two largest EUR AD genome-wide association studies. We next performed pathway enrichment analyses to identify biological mechanisms.

We found 21 proteins and one metabolite colocalized with AD risk that were shared between the EUR and AFR ancestry groups. We also identified 25% AFR and 60% EUR proteins; 50% AFR and 10% EUR metabolites were unique. The pathway enrichment analyses nominated interleukin-1 production and lipid pathway were shared underlying proteomic and metabolomic findings, respectively.

Our findings indicate that these four plasma datasets may pinpoint different effectors of AD risk in diverse populations; findings from AFR participants require validation with AFR-based genome-wide association study data.

For proteomics, 61% of findings for European (EUR) ancestry and 72% for African (AFR) ancestry were not previously reported. For metabolomics, 83% of findings for EUR ancestry and 50% AFR ancestry were not previously reported. Both convergent and divergent pathways were identified in EUR- and AFR-ancestry stratified analyses in either proteomics or metabolomics findings.