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. 2026 Feb 18.
doi: 10.1007/s11357-025-02089-4. Online ahead of print.

Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease

Qi Zeng  1   2   3 , Minghui Wang  1   2   3 , Erming Wang  1   2   3 , Xianxiao Zhou  1   2   3 , Peng Xu  1   2   3 , Vahram Haroutunian  4   5   6   7 , Dongming Cai  8   9 , Bin Zhang  10   11   12   13 ; Members of the Alzheimers Disease Neuroimaging Initiative
Collaborators, Affiliations

Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease

Qi Zeng et al. Geroscience. .

Abstract

Alzheimer's disease (AD) disproportionately affects women and carriers of the apolipoprotein E ε4 allele (APOE4), yet little is known about how sex and APOE interact to influence white matter (WM) integrity during disease progression. We integrated diffusion MRI and matched blood transcriptomic data to investigate these interactions and their underlying biological mechanisms. WM microstructure was quantified using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), and regional vulnerability was assessed with a composite vulnerability score (CVS) derived from associations between diffusion features and AD severity across clinical traits in each of the four sex-APOE groups (female or male, with or without APOE4). Brain parcellation with the Eve atlas revealed regions consistently affected across sex-APOE groups (e.g., parahippocampal and superior temporal gyri) and regions specific to individual groups (e.g., the cingulum in females with APOE4 and the middle frontal gyrus in males without APOE4). Gene co-expression network analysis of the matched blood expression data identified gene subnetworks linked to group-specific regional vulnerability, including a muscle tissue morphogenesis module regulated by NEURL1B and HIST1H2BN associated with middle frontal gyrus vulnerability. These findings demonstrate that sex and APOE genotype jointly shape region-specific WM vulnerability and its molecular signatures in AD. Understanding these interactions provides novel mechanistic insights and may inform precision approaches to drug development, biomarker discovery, and clinical trial design for AD.

Keywords: Alzheimer’s disease; Apolipoprotein E; Diffusion tensor imaging, gene coexpression network analysis; Sex.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study received approval from the local Institutional Review Boards at each participating institution, as documented on the ADNI website. All participants or their authorized representatives provided written informed consent. Conflict of interest: The authors declare no competing interests.

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