APOE -centered transcriptional convergence underlying diverse dementia subtypes
Zhi-Jie Xu, Jie Ma, Guido M. Giuffrè, Jia-Jia Wu, Xin Xue, Juan-Juan Lu, Paolo Maria Rossini, Xu-Yun Hua, Jian-Guang XuBackground
Dementia subtypes exhibit diverse clinical and pathological features, yet may share convergent molecular underpinnings. Identifying these common pathways is critical for unified therapeutic strategies.
Objective
To 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.
Methods
We 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.
Results
We uncovered a shared genetic architecture underlying dementia, identifying 60 novel risk loci.
Conclusions
Our multiscale framework bridges population genetics with molecular pathophysiology, establishing