– Dr FNU Vaibhav
Emerging evidence suggests that the timing of hormone replacement therapy (HRT) initiation could play a pivotal role in modifying Alzheimer’s disease (AD) risk. Dr FNU Vaibhav recently presented the largest meta-analysis to date examining how the timing of HRT influences AD risk. Presented at the 2025 American Neurological Association (ANA) Annual Meeting, the analysis draws from over 50 trials and observational studies, the findings highlight the “critical window” in which oestrogen therapy may offer neuroprotective benefits and the potential risks of late initiation.1
We spoke with Dr FNU Vaibhav (Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, India) to discuss the study rationale, key results, and what clinicians should consider when advising postmenopausal women on HRT use.
Abstract: Vaibhav FNU, et al. Timing-dependent effects of oestrogen therapy on Alzheimer’s disease risk in postmenopausal women: A comprehensive meta-analysis. Presented at: American Neurological Association Annual Meeting 2025; 13–16 September 2025; Baltimore.
Over the past four decades, evidence on HRT and Alzheimer’s risk has been inconsistent. Early observational studies in the 1990s suggested that HRT could reduce risk by 30–45%, but subsequent randomised trials such as the Women’s Health Initiative Memory Study (WHIMS) reported an increased risk of dementia.2 These contradictory results led to confusion among clinicians and researchers.
We undertook this meta-analysis to synthesise all available data and test the “critical window” hypothesis, the idea that the effects of HRT depend on when therapy is started in relation to menopause.1 Our analysis included more than 50 studies, and 8.4 million participants, spanning from the 1980s to 2025, incorporating women who used oestrogen alone, oestrogen plus progestin, or oestrogen with selective oestrogen receptor modulators (SERMs).
Timing appears to be crucial. Women who initiated HRT within five years of menopause showed a 32% reduction in Alzheimer’s risk. Those who began around the time of menopause had a 22% reduction, 29% reduction if started before 60 years of age, while women who started after age 65 experienced a 38% increased risk of developing Alzheimer’s disease.
These data strongly support the timing hypothesis: early initiation may preserve oestrogen’s neuroprotective effects, whereas late initiation may exacerbate neurodegenerative processes.
Across the pooled data, studies with overall oestrogen-only regimens mentioned were analyzed. This showed a reduction with oestrogen by 15%, while combination therapy showed an increased risk with no statistical significance.
Much of this pattern stems from the WHIMS study data, which reported harm with combination HRT, but even when accounting for that, the overall trend persisted.
Our interpretation is that oestrogen alone may confer protective effects, while adding progestin could offset some of those benefits. However, further studies are needed to confirm this in contemporary dosing and delivery formats.
Biomarker and neuroimaging evidence gave valuable mechanistic context. Early or midlife HRT use correlated with 20–40% less tau deposition (as shown by positron emission tomography (PET) and cerebrospinal fluid data) and larger brain volumes, particularly in women carrying the APOE ε2 allele, who had 6–10% greater preserved volume. While women carrying the APOE ε4 allele overall showed an increased risk of AD independently.
Conversely, late-initiated HRT was linked to increased brain atrophy and higher tau burden. These findings suggest that maintaining oestrogen during the perimenopausal years helps sustain neuronal communication, reduce inflammation, and prevent early neurodegenerative changes, effects that may be lost or even reversed when therapy begins too late.
Clinicians should not prescribe HRT specifically to prevent Alzheimer’s disease. However, for women already considering therapy for menopausal symptoms or bone and cardiovascular health, earlier initiation, ideally within five years of menopause, may carry additional neurological benefits.
Starting HRT after age 65 should generally be avoided because of the associated increase in Alzheimer’s risk. Women on therapy should discuss discontinuation after several years and explore proven preventive strategies such as blood pressure control and exercise.
We have now incorporated more studies published in 2025 and there is planning of a large-scale, randomized controlled trial to validate these timing-dependent effects.
Within the next five years, we hope to determine how genetic, hormonal, and biomarker profiles interact, paving the way for more individualized, risk-stratified recommendations for women considering HRT.
Learning points:
- The meta-analysis of >8 million women confirms a timing-dependent relationship between HRT and Alzheimer’s disease risk.
- Early HRT (< 5 years post-menopause) reduced risk by 22–32%, while late initiation (> 65 years) increased risk by 38%.
- Oestrogen-only therapy showed greater protective effects than oestrogen + progestin regimens.
- Early use correlated with lower tau deposition and larger brain volumes, particularly in APOE ε2 carriers.
- HRT should not be used solely for Alzheimer’s prevention but may offer neuroprotective benefits when started early for other indications.
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This content has been developed independently by Touch Medical Media for touchNEUROLOGY. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Source: Vaibhav FNU, et al. Timing-dependent effects of oestrogen therapy on Alzheimer’s disease risk in postmenopausal women: A comprehensive meta-analysis. Presented at: American Neurological Association Annual Meeting; 13–16 September 2025; Baltimore, MD, USA.
Editor: Katey Gabrysch, Editorial Director.
Disclosures: This short article was prepared by touchNEUROLOGY in collaboration with FNU Vaibhav. The content was developed and edited by human editors. No fees or funding were associated with its publication. touchNEUROLOGY utilize AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat). FNU Vaibhav has nothing to disclose in relation to this interview.
Cite: FNU Vaibhav. Timing matters: New data shows early hormone replacement therapy may influence Alzheimer’s risk. touchNEUROLOGY. 04 November 2025.
References:
- Vaibhav FNU, et al. Timing-dependent effects of oestrogen therapy on Alzheimer’s disease risk in postmenopausal women: A comprehensive meta-analysis. Presented at: American Neurological Association Annual Meeting; 13–16 September 2025; Baltimore, MD, USA.
- National Heart, Lung, and Blood Institute. Women’s Health Initiative (WHI). Available at: www.nhlbi.nih.gov/science/womens-health-initiative-whi (accessed 14 October 2025).
- Healio. Hormone replacement therapy timing linked to Alzheimer’s disease risks. Healio Neurology. 15 September 2025. Available at: https://www.healio.com/news/neurology/20250915/hormone-replacement-therapy-timing-linked-to-alzheimers-disease-risks (accessed 14 October 2025).
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