Key takeaways:

• Women with neuropathologic data included 258 with therapy and 2,701 with no therapy.
• Women with therapy had lower risks for clinical dementia diagnoses and memory/functional decline.

Women who used estrogen-only menopausal hormonal therapy later in life had lower risks for neuropathologic and clinical outcomes related to Alzheimer’s disease, according to data published in Neurology.

“As part of an NIH-funded study examining how aging interacts with Alzheimer’s disease, we were particularly interested in sex differences,” Hadi Hosseini, PhD, associate professor of psychiatry and behavioral sciences, Stanford Medicine, told Healio.

Data derived from Bruno J, et al. Neurology. 2026;doi:10.1212/WNL.0000000000218413.

Women represent two-thirds of patients with Alzheimer’s disease and have twice the risk for disease compared with men, Hosseini continued, noting their longer lifespans are not the only cause of these greater odds.

“Several sex-specific, age-related factors may contribute to this disparity, including menopause and the associated decline in estradiol,” Hosseini said.

Previous research into the effect of menopausal hormone therapy (MHT) on risks for outcomes related to Alzheimer’s disease have yielded mixed results, he said.

“One challenge is that many of these studies have relied on clinical diagnoses, which do not always accurately reflect the underlying Alzheimer’s pathology,” Hosseini said.

“We therefore examined the association between MHT use and Alzheimer’s outcomes using postmortem neuropathology — the gold standard for identifying the hallmark brain changes of Alzheimer’s disease,” he said.

In the clinic

The cohort included 19,402 women (mean age at study initiation, 71.9 years; 78% white) from the National Alzheimer’s Coordinating Center (NACC) and 2,058 (mean age at study initiation, 71.1 years; 76.6% white) from the Alzheimer’s Disease Neuroimaging Institute (ADNI).

Among women with available neuropathological outcomes, those with estrogen-only MHT (n = 258) were less likely to have increased neuropathology for Alzheimer’s disease based on National Institute of Aging-Alzheimer’s Association AD Neuropathologic Change (ABC) score than those with no therapy (n = 2,701; OR = 0.65; 95% CI, 0.48-0.88; P = .005).

Also, those with therapy were less likely to develop cerebral amyloid angiopathy (CAA) neuropathology (OR = 0.77; 95% CI, 0.6-0.98; P = .035) and lacunes/infarcts (OR = 0.59; 95% CI, 0.4-0.88; P = .009).

Therapy was associated with decreases in plasma amyloid beta 42/40 (beta = 0.44; 95% CI, 0.16-0.73; P = .0025) and cerebral spinal fluid amyloid beta 1-42 (beta = 0.07; 95% CI, 0.002-0.13; P = .03) as well.

Specific to women in NACC, those with therapy (n = 1,841) were less likely to have a diagnosis of dementia during their last available clinical visit (OR = 0.61; 95% CI, 0.55-0.67; P < .0001) and clinical decline based on Clinical Dementia Rating-Global scales (OR = 0.67; 95% CI, 0.61-0.74; P < .0001) than those with no therapy (n = 17,561).

The women in ADNI who used therapy had increased immediate memory (beta = 0.336; P = .002) and learning (beta = 0.233; P = .033) scores on the Rey Auditory Verbal Learning Test compared with those with no therapy.

Next steps

“Although a definitive diagnosis of AD can only be obtained at autopsy, no previous study to date has measured the association between MHT use and AD-related neuropathological outcomes measured on autopsy data,” Hosseini said.

Adjustments for numbers of APOE e4 alleles, vascular risk factors and other variables may better reveal the impact of treatment on Alzheimer’s development as well, he added.

Looking ahead, the researchers called for prospective trials exploring how this therapy impacts neuroimaging and neuropathologic markers of Alzheimer’s disease to uncover any causality between these associations.

Hosseini also clarified that these findings specifically apply to women with a hysterectomy prior to age 60 years because estrogen-only therapy targets women who do not have a uterus. Other women receive estrogen-plus-progestin.

“For the subset of women who have had a hysterectomy, our results suggest that estrogen-only hormone therapy may have a protective association with Alzheimer’s-related brain changes,” he said.

The observational nature of the study prevents the researchers from attributing these better outcomes to therapy as well, Hosseini added, as other differences between women with and without therapy may have an effect.

“These findings do not change current clinical recommendations, but they do add an important new line of evidence: neuropathological data from autopsied brains,” he said. “This objective, tissue-based assessment is unique in a field of evidence that has historically relied on clinical assessments alone.”

For more information:

Hadi Hosseini, PhD, can be reached at hosseiny@stanford.edu.