MAPT and endothelial dysfunction: Based on our findings and extant literature, we propose an integrated model wherein the female-specific APOE ε4 genotype drives endothelial dysfunction and blood–brain barrier (BBB) disruption (Jiang et al., 2025)—partly via upregulation of hub genes LAMC1, LRP10, RBMS2, and TMOD3—which in turn promotes tau pathogenesis through impaired tau clearance (Langfelder and Horvath, 2008; Xin et al., 2018; Yang et al., 2024) and neuroinflammatory crosstalk (Candelario-Jalil et al., 2022; Ising et al., 2019), collectively facilitating tau accumulation and spread.