Menopause and Brain Health
Alzheimer’s disease (AD), the most common form of dementia, disproportionately affects females. Females have a greater lifetime risk of developing AD than males, and once diagnosed with AD, females decline more rapidly and spend more time in poor health. Despite this, our analysis of 15 years (2009-2023) of Canadian health research showed that only 0.08% of funded projects examined AD in females. Understanding why females are disproportionately affected by AD is necessary for developing targeted interventions to support healthy aging.
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Menopause is characterized by a significant decline in ovarian hormones, and estrogens are critical for forming and maintaining memories. While not every menopausal female will develop AD, menopause is a key aging inflection point that impacts various factors that influence AD risk, including neuroplasticity, cognition, inflammation, metabolic features, and mitochondrial function. Earlier ages of menopause, which correspond with an earlier loss of ovarian hormones, are associated with region-specific increases in tau pathology (an AD neuropathological biomarker) and accelerated cognitive decline in those with higher vascular risk. Moreover, surgically induced menopause, which results in an early and abrupt loss of ovarian hormones, is related to a four-fold increased risk for developing dementia. Importantly, AD pathology begins decades before an AD diagnosis, and the onset of menopause coincides with the onset of AD biomarkers. Given this, the menopause transition may be an important point to intervene with hormone therapy to mitigate the heightened AD risk of females.
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Our research shows that menopausal hormone therapy (MHT) may be a promising intervention. However, its effectiveness depends on several key factors: 1) MHT type, including its formulation, route of administration, dose, and timing relative to the menopause transition, and 2) cognitive domain or how cognitive functioning is assessed (i.e. which tasks) - as each task relies on different brain regions. We found that MHT containing estradiol (E2), the estrogen with the greatest binding to estrogen receptors, benefited AD-sensitive memory tasks only when taken transdermally (as a patch or cream on the skin). In contrast, E2 taken orally (as a pill) did not confer the same benefit, which may be related to how it is metabolized. In fact, ~90% of oral E2 is converted by the liver into estrone (E1), a weaker form of estrogen, while transdermal E2 does not get converted and remains E2. These findings underscore the therapeutic potential of E2 and the importance of understanding the impact of MHT type and route of administration on neuroprotective capacity.
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Beyond MHT type, our work has also shown that the unique life histories of females, including hormonal contraception, pregnancy, stress, and menopause experiences, shape how the brain ages. We found that parity increases neurogenesis in wildtype rats, but decreases neurogenesis in mice with humanized (h) APOEε4 alleles (Lee et al., 2024). This is notable as APOE4 is the greatest genetic risk factor for the onset of late-onset sporadic AD, and E2 benefits are more likely in non-APOE4 carriers - although findings are equivocal. Moreover, hormones modulate inflammatory pathways, and microglia (the brain’s resident immune cells) have emerged as key drivers of female-specific risk for AD, particularly in the hippocampus. Research has reported greater density of microglia and an altered inflammatory response in the hippocampus of female rats with hAPOEε4. In line with this, evidence indicates distinct microglia gene signatures by sex and APOE genotype in the hippocampus that are enriched in pathways related to AD, cellular senescence, and inflammatory signaling. As such, our lab is examining longitudinal changes in pattern separation and microglial activation as endophenotypes of AD in hAPOEε3 and hAPOEε4 mice across different types of menopauses and E2-MHTs. We are also studying how different menopause models (natural, surgical, or chemically-induced) shape spatial transcriptomic signatures in the hippocampus and frontal cortex of hAPOE mice. These studies aim to identify mechanistic pathways that explain why certain females benefit from hormone therapies while others do not.
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In parallel, we are developing novel female-specific AD prediction models using big data and machine learning approaches that integrate overlooked female-specific variables, along with established genetic and modifiable factors. Together, our findings suggest we must abandon a “one size fits all” approach to menopause care, and consider the heterogeneous life experiences of females to determine optimal AD interventions. By embracing this complexity, we aim to inform precision medicine approaches - like tailored MHT care - to support the healthy aging of females.
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This work is funded by Wellcome Leap CARE, Cure Alzheimer's Fund, and Women's Health Access Matters (WHAM)
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