Dementia Risks Vary by Menopause Hormone Therapy Timing, Study Shows

[Hormone Replacement Therapy Timing Emerges as Critical Factor in Reducing Dementia Risk Among Postmenopausal Women]

• Hormone replacement therapy (HRT) use was tied to a reduced risk of dementia in postmenopausal women over 13 years of follow-up.
• Starting HRT between ages 46 and 56 was associated with the strongest dementia risk reduction.
• Benefits also appeared after surgical menopause, for women who carried an APOE4 gene, or for those with lower lifetime estrogen exposure.

Hormone replacement therapy (HRT) was tied to a lower risk of dementia in a prospective study of nearly 185,000 postmenopausal women in the U.K. Biobank.

Over 13 years of follow-up, HRT use was associated with a lower risk of all-cause dementia (HR 0.90, 95% CI 0.84-0.96), according to Anne-Marie Minihane, PhD, of the University of East Anglia in Norwich, England, and colleagues.

Starting HRT between ages 46 and 56 yielded the greatest benefit, Minihane and co-authors reported in Alzheimer’s & Dementia. For all postmenopausal women starting HRT at ages 46 to 50, the HR was 0.87 (95% CI 0.80-0.95, P=0.002); for those starting at ages 51 to 56, the HR was 0.77 (95% CI 0.70-0.86, P<0.001).

Associations emerged for women who had surgical menopause (HR 0.74, 95% CI 0.65-0.84), those who carried an APOE4 gene (HR 0.87, 95% CI 0.80-0.95) and women with lower endogenous estrogen exposure (HR 0.84, 95% CI 0.77-0.93).

The study is the largest of its kind, the researchers noted. The findings supported those of a recent retrospective study that showed women who used estrogen-only menopause hormone therapy had a reduced risk of Alzheimer’s disease.

Women account for nearly two-thirds of cases of Alzheimer’s disease, the main form of dementia, Minihane observed. “In addition to living longer, the reason behind the higher female prevalence is thought to be related to the effects of menopause on brain metabolism and the impact of the main genetic risk factor APOE4 being greater in women,” she said in a statement.

Earlier research suggested that HRT 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 which the FDA removed in 2026.

In the U.S., HRT use declined among postmenopausal women from 26.9% in 1999 to 4.7% in 2020. The treatment continues to be controversial.

The novelty of the U.K. Biobank research is the timing of HRT initiation, said Aimee Spector, PhD, of University College London (UCL), who wasn’t involved with the study.

“This supports the ‘window of opportunity’ hypothesis, suggesting that HRT use during the menopause transition phase, where symptoms are typically more problematic, is important,” Spector wrote on the U.K. Science Media Center website.

“We need very large studies with long-term follow-up to understand whether what happens around menopause relates to brain health later in life,” added UCL’s Sarah James, PhD, who also wasn’t involved with the research.

“The results around surgical menopause and earlier HRT initiation are particularly interesting and provide compelling evidence that timing and individual circumstances matter for the observed relationship with dementia risk,” James wrote on the Science Media Center site.

“The next step is to build on this work: we need to see these findings replicated in more representative populations and with better information about HRT formulation, dose, route, duration, and timing,” she stated.

The U.K. Biobank study followed 183,450 postmenopausal women for an average of 13.3 years, analyzing relationships between women who used HRT for at least 1 year and long-term dementia outcomes. Age at menopause and HRT use were self-reported.

Women with dementia had a mean baseline age of 65; those without dementia were 60 at baseline. In both groups, most women had natural menopause at a mean age of 50.

Overall, 3,948 dementia cases were identified. Of these, 1,993 were Alzheimer’s disease and 1,955 were either “dementia, unspecified” or a non-Alzheimer’s form of dementia. Findings were adjusted for covariates known to influence dementia risk or HRT use.

HRT was associated with a lower risk of Alzheimer’s (HR 0.84, 95% CI 0.77-0.92, P<0.001), but not with non-Alzheimer's dementia (HR 0.95, 95% CI 0.87-1.04, P=0.28), the researchers said.

The U.K. Biobank contains generic HRT information, they acknowledged. Future work should examine how dementia risk may differ by hormone therapy composition, dose, and administration (oral, topical, or vaginal), they noted.

The findings point to varying responses in subgroups of women, highlighting the need for randomized controlled trials to guide HRT prescriptions aimed at lowering dementia risk, they added.

Source link