Sex difference in biological change and mechanism of Alzheimer’s disease: From macro- to micro-landscape

Alzheimer’s disease (AD) is the most common form of dementia and numerous studies reported a higher prevalence and incidence of AD among women. Although women have longer lifetime, longevity does not wholly explain the higher frequency and lifetime risk in women. It is important to understand sex differences in AD pathophysiology and pathogenesis, which could provide foundation for future clinical AD research. Here, we reviewed the most recent and relevant literature on sex differences in biological change of AD from macroscopical neuroimaging to microscopical pathologic change (neuronal degeneration, synaptic dysfunction, amyloid-beta and tau accumulation). We also discussed sex differences in cellular mechanisms related to AD (neuroinflammation, mitochondria dysfunction, oxygen stress, apoptosis, autophagy, blood-brain-barrier dysfunction, gut microbiome alteration, bulk and single cell/nucleus omics) and possible causes underlying these differences including sex-chromosome, sex hormone and hypothalamic-pituitary- adrenal (HPA) axis effects. •AD disproportionally affects women in the development, progression and clinical presentation of AD.•Our review summarized sex differences in biological change of AD from neuroimaging and electrophysiology to pathological change.•Our review summarized sex differences in mechanism from aspects of cellular process, pathogenic molecular and omics.•Sex-chromosome, sex hormone and HPA axis may the account for mechanisms of sex-divergence in AD.