Scientific American May 2020 pp37-41 “The Menopause Connection” “Getting older is the biggest risk factor for Alzheimer’s” “Research indicates that being female is a close second. Why?”
The incidence of Alzheimer’s Disease (AD) trends higher for women and significantly so for women at ages 80, 85, 90 and 95 even after adjusting for women's greater lifespan. Information from PET scans reveals metabolic changes as women approach menopause. Prior to peri-menopause female brains reveal high levels of glucose consumption that fall 15% during peri-menopause and 20-30% after the full onset of menopause. This correlates with the decline of ovarian function-especially the loss of estrogen secretion which is known to regulate metabolism in young females. During the transition to menopause, lasting as many as seven years, more than half of all women experience a temporary cognitive impairment as well. Twenty percent of these women develop AD decades later. Women with longer reproductive intervals-a longer exposure to endogenous estrogen have a lower risk for AD.
3.6 million American females have AD or about one-in-five compared to one-in-nine males. The APOE gene-e4 allele is a risk factor for early-onset AD in females but not males. Given the impact of estrogen should women all get estrogen-replacement? Estrogen is known to regulate glucose transport and mitochondrial energy production. Without sufficient glucose available to the mitochondria, ketones derived from the myelin sheath of nerves are substituted. Drawing on this source reduces conductivity of neurons. As energy falls plaque seems to increase. Estrogen may also regulate the permeability of the blood brain barrier allowing more assaults from toxins and infectious agents which in turn trigger potentially damaging immune responses, more Tau and more Beta Amyloid plaque formation.
Unlike women, Testosterone, which acts similarly to estrogen with respect to metabolism, does not decline precipitously and therefore normal function continues longer with male-aging and the onset of AD happens later.