Global and regional amyloid-β in explaining APOE-ε4 and sex associations with medial temporal tau: a neuropathology study

Abstract The medial temporal lobe (MTL) is a key region in Alzheimer’s disease (AD) pathogenesis, affected early by tau pathology. While female sex and APOE-ε4 are two known risk factors that affect tau levels, whether these factors drive tau in the MTL via amyloid-dependent or amyloid-independent mechanisms remains unclear. We investigated these relationships in two large neuropathological cohorts comprising 2550 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP; n =1587, main cohort) and Arizona Study of Aging and Neurodegenerative Disorders (AZSAND; n=963, replication cohort) covering the whole AD continuum. Neuropathological assessments of global neocortical and regional MTL amyloid-β burden were used to determine the extent to which amyloid-β pathology mediated associations of APOE-ε4 carriership and sex with MTL tau burden. In both cohorts, APOE-ε4 carriership and female sex were associated with significantly greater MTL tau pathology (all p <0.001). Adjustment for global amyloid-β attenuated but did not eliminate these associations ( p ≤0.024). However, after jointly accounting for global and MTL amyloid-β burden, the association between APOE-ε4 and MTL tau was no longer significant in either cohort ( p ≥0.19), whereas the association between female sex and MTL tau remained robust ( p ≤0.004). Models incorporating both global and regional MTL amyloid-β explained substantially more variance in MTL tau burden than models including only global amyloid-β, and results were replicated when further adjusting for diagnostic group or neocortical tau burden. These findings suggest that APOE-ε4 and female sex influence MTL tau accumulation through partially distinct pathogenic pathways, supporting an additional contribution of regional amyloid-β to the APOE-ε4-associated MTL tau burden while implicating additional amyloid-independent mechanisms in female vulnerability to tau accumulation.