FAQs On The Critical Window Hypothesis for Menopausal Hormone Therapy's Neuroprotective Effects

The critical window hypothesis has emerged as a focal concept in understanding whether hormone therapy (HT)—especially estrogen replacement—can deliver neuroprotective benefits and reduce cognitive decline risk in postmenopausal women.

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New data from a secondary analysis of the Early vs Late Intervention Trial with Estradiol (ELITE) have shed new light on the subject, suggesting that initiating estradiol within 6 years of menopause may influence key Alzheimer disease plasma biomarkers, whereas later initiation appears less effective. Investigators reported that MHT showed no effect on biomarkers in women who were 10 or more years past menopause. In an interview with Patient Care during The Menopause Society (TMS) 2025 Annual Meeting, October 21-25, analysis coauthor Roksana Karim, MD, PhD, professor of clinical population and public health sciences at the Keck School of Medicine of USC, in Los Angele, CA, noted that their results lend partial support to the critical window hypothesis, and underscore the need for larger confirmatory studies. You can read the full Karim interview here. Following are frequently asked questions about the hypothesis along with answers culled from the most recent literature.

Q: What is the critical window hypothesis in hormone therapy for cognition?

A: The critical window hypothesis posits that hormone therapy’s neuroprotective effects against cognitive decline can only be achieved if HT is initiated during a narrow window near the onset of menopause—typically within 10 years, or before age 60. The concept is based on evidence that estrogen’s neurobiological actions—such as promoting synaptic plasticity, neurogenesis, and supporting hippocampal function—are most effective in the early postmenopausal period, but may lose efficacy or even become detrimental if begun much later.1-3​

Q: What is the biological rationale behind this hypothesis?

A: Estrogen is crucial for maintaining synaptic connectivity and neurogenesis, particularly in brain regions integral to memory and executive function (e.g., hippocampus and prefrontal cortex). Animal studies show that estrogen deprivation accelerates neuronal aging and vulnerability to Alzheimer’s-related pathology, but timely estrogen restoration can reduce amyloid accumulation and preserve brain structure. This suggests a period shortly after menopause when neurons remain responsive to estrogen, forming the mechanistic basis of the critical window.3,4​

Q: What clinical evidence supports the critical window hypothesis?

A: Multiple observational studies and several randomized controlled trials indicate that HT started soon after menopause may reduce the risk of Alzheimer’s disease (AD) and support cognitive performance. Meta-analyses suggest HT is most beneficial when prescribed in proximity to menopause, reinforcing the timing effect. Conversely, initiation of HT in women aged 65 and older has less clear benefit and may be associated with adverse outcomes, as first highlighted by the Women's Health Initiative Memory Study (WHIMS).5,6 ​

Recent long-term studies, such as the Kronos Early Estrogen Prevention Study (KEEPS) and its cognitive substudies, found no evidence of harm to cognition with short-term, early HT initiation and reported modest mood benefits.7 MRI and PET imaging further support biological plausibility, showing enhanced hippocampal and prefrontal structure in early HT users, and increased tau and amyloid pathology in late initiators.8​

Q: Are there specific hormone formulations or regimens implicated?

A: Evidence is mixed regarding HT formulations. Early initiation of estrogen-only regimens appears most protective, while continuous conjugated equine estrogen/medroxyprogesterone acetate (CEE/MPA) has shown risk of cognitive decline regardless of timing. Combined estradiol-progestin formulations show tentative support for neuroprotection in small trials, but more study is required to clarify their risk-benefit profile.1,5​

Q: What about surgical menopause and timing of HT?

A: For women undergoing oophorectomy before natural menopause, initiating HT near the time of surgery may mitigate cognitive risks associated with abrupt estrogen loss. A recent meta-analysis found the neuroprotective effects of HT were strongest in women experiencing surgical menopause at a young age, when estrogen was replaced soon after ovary removal.9​

Q: Does later initiation of HT confer any cognitive benefit?

A: No strong evidence supports HT’s neuroprotective effect when therapy is initiated several years after menopause. Older age at start or greater time since menopause is linked with neutral or adverse cognitive outcomes, including increased tau burden and dementia risk. The “healthy cell bias” hypothesis complements the timing concept, suggesting that hormone therapy may only benefit neurons that remain healthy—further highlighting the window’s neurobiological limitations.4,5,8 ​

Q: How have guidelines responded to these findings?

A: Clinical guidelines increasingly recommend initiating menopausal hormone therapy within 10 years of menopause or prior to age 60, if cognitive protection is a consideration. They caution that hormone therapy should generally not be started for cognitive protection in women much older than this or more than a decade post-menopause.2

Q: What are the main research limitations and future directions?

A: Research is challenged by HT formulation heterogeneity, variability in cognitive outcome measures, and differences in study populations. Large, long-term randomized trials in diverse populations and more sophisticated neuroimaging studies are needed to confirm the optimal timing, regimen, and the duration of protective effects. Differential effects by etiology of menopause (natural vs surgical) and genetic risk factors (e.g., APOE ε4) also require ongoing investigation. 1,9,10​

References

1. Maki PM. Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies. Menopause. 2013;20(6):695‑709. doi:10.1097/GME.0b013e3182960cf8
2. Taylor S, Davis SR. Is it time to revisit the recommendations for initiation of menopausal hormone therapy? Lancet Diabetes Endocrinol. 2025;13(1):69‑74.
3. Mervosh N, Devi G. Estrogen, menopause, and Alzheimer’s disease: understanding the link to cognitive decline in women. Front Mol Biosci. 2025;12:1634302. doi:10.3389/fmolb.2025.1634302
4. Guo H, Liu M, Zhang L, et al. The critical period for neuroprotection by estrogen replacement therapy and the potential underlying mechanisms. Curr Neuropharmacol. 2020;18(6):485‑500. doi:10.2174/1570159X18666200123165652
5. Nerattini M, Jett S, Andy C, et al. Systematic review and meta‑analysis of the effects of menopause hormone therapy on risk of Alzheimer’s disease and dementia. Front Aging Neurosci. 2023;15:1260427. doi:10.3389/fnagi.2023.1260427
6. Coughlan GT, Betthauser TJ, Boyle R, et al. Association of age at menopause and hormone therapy use with tau and β‑amyloid positron emission tomography. JAMA Neurol. 2023;80(5):462‑473. doi:10.1001/jamaneurol.2023.0455
7. Gleason CE, Dowling NM, Kara F, et al. Long‑term cognitive effects of menopausal hormone therapy: findings from the KEEPS continuation study. PLoS Med. 2024;21(11):e1004435. doi:10.1371/journal.pmed.1004435
8. Coughlan GT, Rubinstein Z, Klinger H, et al. Associations between hormone therapy use and tau accumulation in brain regions vulnerable to Alzheimer’s disease. Sci Adv. 2025;11(10): eadt1288. doi:10.1126/sciadv.adt1288
9. Watts A, Donofry S, Ripperger H, Eklund NM, Wan L, Kang C, Grove G, Oberlin LE, Gujral S, Vidoni ED, Burns JM, McAuley E, Hillman CH, Kramer AF, Kamboh MI, Erickson KI. Lifetime estrogen exposure and domain‑specific cognitive performance: results from the IGNITE study. Front Aging Neurosci. 2025;17:1524474. doi:10.3389/fnagi.2025.1524474 (Frontiers)
10. Rocca WA, Kantarci K, Faubion SS. Risks and benefits of hormone therapy after menopause for cognitive decline and dementia: a conceptual review. Maturitas. 2024;184:108003. doi:10.1016/j.maturitas.2024.108003