Project Type(s):
Basic Science

Variants in the apolipoprotein E (APOE) gene strongly influence Alzheimer’s disease (AD) risk, neuropathology, and longevity. The APOE ε4 allele confers the greatest genetic risk for AD in Europeans and Japanese populations and is associated with reduced lifespan, whereas the protective ε2 allele is enriched among centenarians. Notably, APOE ε4 risk is attenuated in individuals of African ancestry, who also show reduced neuropathologic burden. We hypothesize that ancestry-specific regulatory variation at the APOE locus alters risk allele dosage and contributes to these differences. Single-nucleus RNA-seq studies show reduced APOE ε4 expression in astrocytes of African carriers, but the underlying regulatory variants remain unknown. This proposal aims to define the APOE transcript repertoire in human brain (Aim 1) and functionally evaluate ancestry-enriched APOE variants for effects on transcription, splicing, and RNA processing (Aim 2) using targeted long-read RNA sequencing and multiplex reporter assays. This work will generate a regulatory map of APOE and identify variants that lower APOE expression and protect against AD.

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