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Sex and Female-Specific Experiences: Alzheimer's Disease

Major risk factors for AD are age, APOEε4 alleles and female sex. Women with AD show smaller hippocampi, greater AD neuropathology and steeper cognitive decline than men. Women with APOEε4 alleles have a greater risk to develop AD earlier, show greater cognitive decline and higher ptau levels than men with APOEε4 alleles and women without APOEε4 alleles (Duarte-Guterman et al., 2021). Hippocampus integrity is compromised early in AD, and existing sex differences in the hippocampus may contribute to the greater susceptibility in females to develop AD. The hippocampus retains the ability to form new neurons in adulthood, and these new neurons play a role in cognition and AD. Our lab has found dramatic sex differences in the capacity for neurogenesis as males have faster maturation and more neural stem cells (Sox2) in the dorsal hippocampus (Yagi et al., 2020). Reduced Sox2 expression, which is mediated by survivin, is linked to cognitive deficits in aging and AD. Immune system signaling regulates hippocampal neurogenesis, influences cognition, is disrupted in AD, and modified by sex. Microglia activation in AD contributes to synaptic and neuronal loss in aging via excessive synaptic pruning, mediated by the complement system which is elevated in females and with aging. Our goal is to determine whether sex differences in Sox2 expression and hippocampal neurogenesis dynamics are influenced by aging and APOEε4 genotype, and contribute to cognition and neuropathology. This work is supported by Cure for AD.

Females have a greater burden of Alzheimer’s Disease (AD) and experience greater cognitive decline than men with AD. Females face unique physiological challenges that may affect AD manifestation and treatment. Pregnancy and motherhood (parity) play an important role in the female aging brain. Increasing parity is associated with a greater risk of AD, AD neuropathology, obestity (linked to AD), and an earlier age of AD onset that interacts with APOE genotype. Declining estrogens in females are associated with cognitive decline, increased risk for AD, neuroinflammation and reduced metabolism. Hormone therapy (HT) can improve cognition, metabolism, and reduce neuroinflammation, but HT benefits depend on age, type of HT, genotype, and previous parity. Furthermore, neuroinflammation and metabolic disorders are evident with AD and our research shows that parity affects inflammation, genes related to metabolism, and the ability of HT to influence neuroinflammation later in life. The goal of this work is to determine the mechanisms by which parity and genetics affect how the female aging brain responds to hormone therapy, immune, and metabolic challenges. The integrity of the hippocampus, including neurogenesis, influences cognitive decline and AD risk. Aging, parity, HT, neuroinflammation, and metabolic challenges in turn modulate hippocampal neurogenesis, suggesting a previously unexplored connection between these factors.

Our new study points to some surprising effects of previous pregnancy on neurogenesis and Sox2 expression in the hippocampus (Lee et al., bioRxiv). This work is supported by CIHR.

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