Menopause and Mitochondria: Windows into Estrogen Effects on Alzheimer's Disease Risk and Therapy

Metabolic derangements and oxidative stress are early events in Alzheimer's disease pathogenesis. Multi-faceted effects of estrogens include improved cerebral metabolic profile and reduced oxidative stress through actions on mitochondria, suggesting that a woman's endogenous and exogenous estrogen exposures during midlife and in the late post-menopause might favourably influence Alzheimer risk and symptoms. This prediction finds partial support in the clinical literature. As expected, early menopause induced by oophorectomy may increase cognitive vulnerability; however, there is no clear link between age at menopause and Alzheimer risk in other settings, or between natural menopause and memory loss. Further, among older post-menopausal women, initiating estrogen-containing hormone therapy increases dementia risk and probably does not improve Alzheimer's disease symptoms. As suggested by the 'critical window' or 'healthy cell' hypothesis, better outcomes might be expected from earlier estrogen exposures. Some observational results imply that effects of hormone therapy on Alzheimer risk are indeed modified by age at initiation, temporal proximity to menopause, or a woman's health. However, potential methodological biases warrant caution in interpreting observational findings. Anticipated results from large, ongoing clinical trials [Early Versus Late Intervention Trial with Estradiol (ELITE), Kronos Early Estrogen Prevention Study (KEEPS)] will help settle whether midlife estrogen therapy improves midlife cognitive skills but not whether midlife estrogen exposures modify late-life Alzheimer risk. Estrogen effects on mitochondria adumbrate the potential relevance of estrogens to Alzheimer's disease. However, laboratory models are inexact embodiments of Alzheimer pathogenesis and progression, making it difficult to surmise net effects of estrogen exposures. Research needs include better predictors of adverse cognitive outcomes, biomarkers for risks associated with hormone therapy, and tools for monitoring brain function and disease progression.