The histone variant H2A.Z regulates sex differences in Alzheimer's disease pathophysiology

Alzheimer's disease (AD) disproportionately affects women, yet mechanisms underlying this sex difference remain unclear. Histone variants are overrepresented components of aging neuronal chromatin, but their contribution to AD is unknown. Here, we identify the histone variant H2A.Z as a sex-specific regulator of AD in the postmortem human hippocampus and in 5xFAD mice. H2A.Z occupancy decreased in female but increased in male AD patients. In females, reduced H2A.Z occupancy at the transcription start site (TSS) occurred despite increased total H2A.Z, indicating that H2A.Z is redistributed to sites of lower H2A.Z occupancy. Similar sex-dependent alterations were observed in 5xFAD mice over disease progression. Whereas H2A.Z.1 depletion improved memory and AD pathology in females at early and late disease stages, it impaired memory in male mice at early stages and improved memory in late stages. Together, these data identify H2A.Z as a regulator of sex- and stage-dependent AD outcomes, with implications for the sex-specific therapeutic targeting of chromatin factors.