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Alzheimer’s disease (AD) disproportionately affects females and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be sex-specific. Using the ADNI database, we analysed the effect of sex and APOE genotype and sex and diagnosis (cognitively normal (CN), MCI, AD) on: AD-related endpoints (cognition, hippocampal volume, amyloid beta, tau-pathology), immune, neuroplasticity, and stress markers, and blood epigenetic age. More males were diagnosed with MCI but there was no sex difference in those diagnosed with AD, suggesting the progression from CN, MCI to AD may be sex-specific. Several biomarkers may influence sex differences in incidence and progression of MCI and AD. We found that females had higher levels of plasma CRP and lower levels of CSF IL-8, IL-16, IgA, and ICAM1 than males. Increasing number of APOE ε4 alleles and diagnosis also decreased plasma CRP in both sexes. Sex, diagnosis, or APOE genotype did not affect epigenetic age acceleration. We found, consistent with other studies, that females had higher levels of CSF tau-pathology that was disproportionately affected by APOE genotype compared to males. Females also had better memory (including verbal) scores than males, which may suggest a delay in the onset of cognitive decline or diagnosis. Sex differences in immune biomarkers and hippocampal volume (direction was dependent on method of correction) indicate that the underlying physiology during aging may be sex-dependent.

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused one, two or three weeks after BrdU injection, marking newly dividing cells. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than females. Males had a greater reduction in neurogenesis between one and two weeks after mitosis, while females showed similar levels of neurogenesis throughout. The faster maturation and attrition of new neurons suggests greater potential for neurogenesis to respond to external stimuli in males compared to females and emphasizes the importance of studying sex on adult hippocampal neurogenesis.