Sex and APOE genotype‐specific white matter changes in Alzheimer’s disease

Abstract

Background: APOE ε4 genotype and sex difference represent strong risk factors for Alzheimer’s Disease (AD) that also lead to white matter (WM) microstructural changes. However, it is still not clear which brain regions have the strongest changes with APOE ε3 and ε4 allele carrier status and sex difference, and what are the key drivers and biological pathways underlying WM abnormality during disease progression. In this study, we present a new comprehensive framework to identify sex‐ and APOE genotype‐specific WM changes in specific brain regions with AD severity using the data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐GO/2). Method: DTI‐derived features including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), radial diffusivity (RD) were calculated from ADNIGO/2 (N = 232). ADNI participants were classified depending on their sex and APOE genotype status as female APOE ε3/3, male APOE ε3/3, female APOE ε4 positive, and male APOE ε4 positive. Through correlating DTI features with the clinical/cognitive traits, we systematically rank‐ordered 176 brain regions in relation to disease severity for each group. Multiscale Embedded Gene co‐Expression Network Analysis (MEGENA) was performed using processed expression data to identify clusters of highly correlated genes and DTI‐features as modules. Gene Set Enrichment Analysis (GSEA) was carried out to annotate each module with enriched pathways for each group. Result: The parahippocampal gyrus (PHG)‐right, posterior thalamic radiation (PTR)‐left, hippocampus (HIPPO)‐left, and the superior temporal gyrus (STG)‐right were top‐ranked regions with sex and APOE ε3 and ε4 alleles carrier status (Figure 1A‐D). WM changes in PTR‐right are the only specific for the male APOE ε4+ group compared to the other groups. PHG‐right is highly associated with worse AD clinical outcomes in APOE ε4 allele carriers regardless of sex difference. DTI features in MTWM‐left is significantly correlated with only female APOE ε3 group. Besides, the immune system, mitochondrial regulation, and myeloid cell differentiation are among the pathways enriched with modules in different sex and APOE genotype groups in top brain regions (Table 1). Conclusion: Enhanced understanding of the biological processes and key drivers related to sex‐ and APOE genotype‐specific WM microstructural changes could lead to novel therapeutic strategies for AD.