- Estrogen-only menopausal hormone therapy was linked with reduced Alzheimer’s pathology in an autopsy study.
- Estrogen treatment was also tied to lower odds of dementia diagnosis.
- More than 20 years after the landmark Women’s Health Initiative trial, hormone replacement therapy remains controversial.
Women who used estrogen-only menopausal hormone therapy (MHT) had a reduced risk of Alzheimer’s disease, according to a retrospective longitudinal study.
Estrogen-only MHT users had lower odds of increased Alzheimer’s pathology on autopsy compared with non-users (OR 0.65, 95% CI 0.48-0.88, P=0.005), reported Jennifer Bruno, PhD, of Stanford University in California, and co-authors.
Estrogen therapy was linked to less amyloid pathology in plasma (β = 0.44, 95% CI 0.16-0.73, P=0.0025) and cerebrospinal fluid (β = 0.07, 95% CI 0.002-0.13, P=0.030), they noted in Neurology.
It was also tied to lower odds of both dementia diagnosis (OR 0.61, 95% CI 0.55-0.67, P<0.0001) and memory or functional decline symptoms (OR 0.67, 95% CI 0.61-0.74, P<0.0001).
“MHT appears to exert a modest but meaningful and statistically significant protective effect on the risk of developing Alzheimer’s pathology,” Bruno said in a news release.
“For a long time, the going recommendation was ‘Don’t use MHT for memory decline,'” she stated. “This study flies in the face of that recommendation.”
Early research had suggested that MHT might protect against Alzheimer’s and cardiovascular disease, but in 2003, the Women’s Health Initiative Memory Study (WHIMS) reported that estrogen-plus-progestin formulations increased probable dementia risk in women ages 65 or older.
The Women’s Health Initiative trial also linked combined estrogen and progestin to higher breast cancer and heart disease risks, leading to black-box warnings that the FDA removed in February.
MHT use among postmenopausal women declined from 26.9% in 1999 to 4.7% in 2020 and continues to be controversial.
“Few questions in cognitive aging are as prone to oversimplification as the relationship between MHT, Alzheimer’s disease, and dementia,” observed Simone Salemme, MD, of the University of Modena and Reggio Emilia in Italy, in an accompanying editorial.
“Yet, MHT is not a single exposure: It differs by timing, regimen, route, indication, and population,” Salemme pointed out.
“The field now needs a biologically ambitious and clinically grounded research agenda that is attentive to the social and health care contexts shaping real-world access and use; follows women across the menopause-to-dementia life course; integrates biomarkers, neuropathology, and cognition; and captures detailed exposure histories,” he wrote. “The next research question should be for whom, when, and under what conditions MHT may shape later-life brain health.”
Bruno and co-authors studied 21,462 women from two groups: the National Alzheimer’s Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Participants were women ages 50 and older, with self-reported use of oral estrogen-only MHT, which generally is prescribed for women without a uterus, or without MHT use. Topical estrogen users were not included in the study.
Overall, 1,953 women used estrogen-only MHT and 19,509 did not. Women started MHT after age 70 on average. They were followed for approximately 3 to 6 years.
The primary outcome was pathology assessed by the NIA-AA Alzheimer’s Disease Neuropathologic Change ABC score, an autopsy measurement of amyloid-beta deposits, Braak-stage neurofibrillary tau tangles, and CERAD neuritic plaques.
The NACC neuropathologic cohort provided autopsy data for 258 MHT users and 2,701 non-users. In both groups, women died at age 82 on average. Outcomes were adjusted for age, education, race, hypertension, and APOE genotype.
“Our findings are most directly applicable to the minority subset of women who have undergone hysterectomy and may be prescribed unopposed estrogen,” Bruno and colleagues noted. “Therefore, the generalizability of our results to the broader population of MHT users is substantially limited.”
NACC and ADNI did not systematically collect hysterectomy data, but recent CDC survey data indicated that 35% of women ages 65 to 74 have had a hysterectomy.
Participants who used hormone therapy had an average age of 70 in this study, a variance from the current practice of starting therapy when women are in their late 40s to early 50s and stopping it before age 60, the researchers acknowledged. The study was observational, and unmeasured confounders may have influenced results.
“Despite these limitations, our findings provide evidence of an association between use of estrogen-only hormone therapy during later life and better outcomes on dementia and brain health,” Bruno said.
