APOE-centered transcriptional convergence underlying diverse dementia subtypes.

Abstract

BackgroundDementia subtypes exhibit diverse clinical and pathological features, yet may share convergent molecular underpinnings. Identifying these common pathways is critical for unified therapeutic strategies.ObjectiveTo delineate the shared genetic architecture and convergent molecular pathways underlying diverse dementia subtypes, and to mechanistically characterize the structural and functional impacts of key risk variants, thereby establishing a unified framework for precision therapeutic development.MethodsWe applied multivariate genomic structural equation modeling to six dementia-related genome-wide association studies (GWAS), followed by integrative transcriptome-wide association studies (TWAS) across tissues and cell types. We combined AlphaFold3-predicted structures, molecular dynamics simulations, and deep learning-based stability analyses to assess functional impacts of risk variants.ResultsWe uncovered a shared genetic architecture underlying dementia, identifying 60 novel risk loci. APOE emerged as the central hub, linking lipid metabolism and immune dysregulation. Missense variants in APOE (p.Arg176Cys), BIN2 (p.Glu190Lys), and FOXO1 (p.Asp82His/Tyr/Asn) induced charge-dependent conformational destabilization, impairing lipid transport, microglial phagocytosis, and transcriptional control.ConclusionsOur multiscale framework bridges population genetics with molecular pathophysiology, establishing APOE-centered transcriptional dysregulation as a unifying mechanism in dementia. These findings nominate convergent pathways, particularly lipid-immune crosstalk, as high-priority targets for precision therapeutics.