Estrogen enhances synaptic connectivity through promotion of long-term potentiation (LTP), increased dendritic spine density, and heightened expression of synaptic proteins important for synaptic plasticity (Toran-Allerand et al., 1999; Henderson et al., 2016; Smejkalova and Woolley, 2010). These effects are especially pronounced in the hippocampus and prefrontal cortex—regions integral to working memory, spatial navigation, and executive function (Shanmugan and Epperson, 2014). Estradiol also stimulates adult neurogenesis in the dentate gyrus, a capacity that declines with age and estrogen deprivation (Barha and Galea, 2010; Grodstein et al., 2003). These synaptic and neurogenic effects underlie the cognitive advantages observed in premenopausal women and in animal models treated with estradiol (Mishra et al., 2023).

In mouse models, early ovarian failure during perimenopause enhances astrocyte activation and regional amyloid accumulation in the hippocampus during early-stage cerebral amyloid angiopathy, suggesting emerging neurovascular dysfunction, which is often correlated with the development of dementia (Platholi et al., 2023). Another mouse model study found that chemically induced perimenopause in mice with early-stage Alzheimer’s pathology increased amyloid-beta accumulation and heightened astrocyte and microglial activation in specific hippocampal subregions, although cognitive deficits were not yet apparent. These results support the idea that perimenopause represents a critical window of emerging vulnerability to Alzheimer’s-related brain changes where intervention may be beneficial (Marongiu et al., 2025).

Estrogen exerts widespread influence on neurotransmitter systems critical to cognition, mood regulation, and behavioral flexibility—many of which are vulnerable to age-related decline and prominently implicated in AD. Estrogen receptors are expressed not only in cortical and hippocampal neurons but also in neurons producing acetylcholine and monoamines, including serotonin, dopamine, and norepinephrine (Ma et al., 2016; Ross and Van Bockstaele, 2021).

• Acetylcholine: Estrogen upregulates choline acetyltransferase, the enzyme responsible for acetylcholine synthesis, and enhances muscarinic receptor density in the basal forebrain and hippocampus. It also supports the integrity of cholinergic projections—among the earliest to deteriorate in AD—thereby preserving attention and memory processes. This cholinergic support underpins estrogen’s role in attention and memory (Russell et al., 2019; Newhouse and Dumas, 2015). The loss of this estrogenic support during perimenopause may compromise cholinergic tone and contribute to the early cognitive symptoms observed in prodromal AD (Kwakowsky et al., 2016).

Through this multifaceted support of key neurotransmitter systems, estrogen maintains the neurochemical infrastructure essential for cognitive and emotional regulation. The loss of estrogenic signaling during perimenopause may destabilize these systems, creating a period of heightened vulnerability to the neuropathological processes underlying Alzheimer’s disease.

Mitochondria are central to neuronal metabolism, and their dysfunction is a key feature of aging and Alzheimer’s disease (McGill Percy et al., 2025). Estrogen enhances mitochondrial biogenesis, increases ATP production, and reduces oxidative stress through upregulation of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase (Lejri et al., 2018; Velarde, 2013). This contributes to reduced accumulation of reactive oxygen species, which are implicated in both amyloid aggregation and tau hyperphosphorylation.

Estrogen influences amyloid precursor protein processing by promoting α-secretase activity and suppressing β-secretase, thereby favoring the non-amyloidogenic pathway (Cole and Vassar, 2007). In vivo models show that estrogen administration reduces Aβ levels and plaque formation and may reduce tau formation in post-menopausal women (Wang et al., 2024a; Henderson, 2014). Additionally, estrogen modulates kinases involved in tau phosphorylation, thereby mitigating neurofibrillary tangle development (Kantarci et al., 2016; Wang et al., 2024b; Depypere et al., 2023).

Estrogen has vasoprotective effects, including the promotion of nitric oxide synthesis, improved endothelial function, and preservation of cerebral autoregulation (McNeill et al., 2002). It also maintains blood-brain barrier integrity, reducing permeability and neuroinflammatory infiltration (Maggioli et al., 2016). With estrogen loss, particularly during the menopausal transition, cerebral perfusion diminishes and the BBB becomes more vulnerable—conditions that may synergize with amyloid and vascular pathology to accelerate cognitive decline (Russell et al., 2019; Maggioli et al., 2016).

Microglia and astrocytes express estrogen receptors and are directly modulated by hormonal signaling (Mor et al., 1999). Estrogen promotes an anti-inflammatory glial phenotype, downregulates pro-inflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α), and restrains chronic neuroinflammation—a hallmark of aging and AD (Mor et al., 1999; Villa et al., 2016). Estrogen deprivation in menopause may shift this balance toward a pro-inflammatory state, thereby exacerbating neuronal injury and synaptic loss (Villa et al., 2016).

Early observational studies suggested a strong protective association between estrogen use and reduced AD risk. For example, data from the Cache County Study, which included persons aged 65 years or older, and the Baltimore Longitudinal Study on Aging, which included postmenopausal women ages 65 and older, indicated that women who used HT near the time of menopause had a lower incidence of AD (Shao et al., 2012; Nerattini et al., 2023). However, these studies were limited by healthy-user bias and lack of randomization.

The critical window hypothesis emerged from such findings, suggesting that the brain may retain estrogen sensitivity during a finite period following ovarian hormone withdrawal (Sherwin, 2009). Beyond this window, estrogen receptors may downregulate, and the brain may enter a pro-inflammatory, vulnerable state that does not respond favorably to exogenous hormones.

Randomized controlled trials have yielded mixed results and are briefly summarized in Table 2. The Women’s Health Initiative Memory Study (WHIMS) remains the most widely cited trial in the field Espeland et al. (2024). In this large, randomized controlled trial (RCT) of women aged 65 and older, conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increased the risk of dementia and cognitive decline. However, this trial enrolled women well beyond the menopausal transition (mean age 69), raising questions about generalizability to midlife populations. Additionally, while there was an increased risk of all-cause dementia (including normal pressure hydrocephalus, for example,), there was NOT an increased risk for AD (Nerattini et al., 2023).

Subsequent RCTs have painted a more nuanced picture:

• The KEEPS-Cog trial studied younger postmenopausal women (ages 42–58) and found no adverse cognitive effects of transdermal estradiol over 4 years, although it was not powered to detect AD incidence (Gleason et al., 2015).

Not all estrogens or regimens are equivalent. The WHIMS trial employed oral CEE, a formulation derived from pregnant mare’s urine, along with MPA, a synthetic progestin Espeland et al. (2024); Shumaker et al., 2004). In contrast, bioidentical 17β-estradiol—particularly via transdermal routes—may have more favorable effects on cognition and cardiovascular health. Oral estrogens undergo first-pass hepatic metabolism, increasing coagulation factors and inflammatory markers, whereas transdermal estradiol bypasses the liver and maintains a more physiologic estrogen profile (Kantarci et al., 2016; Wharton et al., 2011).

Progestin co-administration further complicates interpretation. While necessary for endometrial protection in women with a uterus, synthetic progestins like MPA may attenuate estrogen’s beneficial effects (Stanczyk et al., 2013). Natural micronized progesterone appears to have a more favorable safety and neurocognitive profile but has not been extensively studied in long-term AD prevention trials.

These differences were directly explored in the Kronos Early Estrogen Prevention Study (KEEPS), which randomized healthy recently postmenopausal women (median age 42–58 years old; within 3 years of menopause) to either oral CEE, transdermal 17β-estradiol, or placebo, all with cyclic micronized progesterone (Gleason et al., 2015; Gleason et al., 2024). The KEEPS-Cog sub-study evaluated cognitive outcomes over 4 years and found no cognitive benefit from either formulation compared to placebo. Although neither route caused harm, the anticipated cognitive enhancement—particularly from transdermal estradiol—was not observed, challenging assumptions that bioidentical transdermal therapy would outperform CEE in preserving cognitive function (Gleason et al., 2024).

A long-term follow-up study of the KEEPS cohort approximately 10 years after cessation of therapy similarly found no lasting benefit or harm on cognitive outcomes from either hormone regimen. These findings suggest that in healthy, low-risk women, even early HT initiation may be cognitively neutral, and that timing, formulation, and population risk profile all influence therapeutic outcomes (Gleason et al., 2024).

This nuanced evidence underscores the importance of tailoring hormone therapy—not only in terms of age and timing, but also formulation, route, and individual risk factors, including cardiovascular and genetic vulnerability.

Despite promising mechanistic data, current clinical trials remain underpowered, short in duration, and heterogeneous in design. Most have not targeted women at the highest risk—those with metabolic syndrome, cerebrovascular pathology, or APOE-ε4 genotype (Saleh et al., 2023). Furthermore, outcomes have focused on global cognition rather than sensitive biomarkers such as amyloid PET imaging, tau load, white matter hyperintensity volume, or regional perfusion.

Another prospective cohort of women tracked from midlife to late life, early initiation of hormone therapy—particularly within 5 years of menopause—was associated with reduced risk of cognitive impairment and dementia. Notably, the protective association was strongest in APOE-ε4 non-carriers, whereas APOE-ε4 carriers did not appear to benefit and, in some cases, showed potential harm with later or prolonged hormone use (Taxier et al., 2022a).

This study reinforces both the critical window hypothesis and the need for genotype-informed HT decision-making, aligning with other studies showing that APOE-ε4 carriers may have heightened sensitivity to hormonal and metabolic stressors. These findings argue for tailoring both timing and duration of hormone therapy to genetic and vascular risk (Saleh et al., 2023; Taxier et al., 2022a).

Such observational data, while subject to confounding factors, offer valuable direction for future trials and underscore the need for stratified prevention strategies.

Estrogen plays a central role in maintaining cerebrovascular health through its effects on endothelial function, nitric oxide production, arterial compliance, and blood-brain barrier (BBB) integrity (Maggioli et al., 2016). With the menopausal transition, the decline in estrogen leads to increased arterial stiffness, endothelial dysfunction, and enhanced vulnerability to ischemic injury. These vascular changes may precede or exacerbate neurodegenerative processes, particularly in women with underlying metabolic or hypertensive risk (Hodis et al., 2016).

Women also appear to have greater WMH burden than men for a given vascular risk profile, and WMHs are a well-established predictor of cognitive decline, especially executive dysfunction and processing speed—domains often affected early in women with AD (Hodis et al., 2016).

Vascular dysfunction may synergize with amyloid and tau pathology to accelerate neurodegeneration. Chronic hypoperfusion impairs glymphatic clearance of Aβ, while blood-brain barrier breakdown facilitates neuroinflammation and toxic protein accumulation. Additionally, microvascular disease may sensitize neurons to injury from tau hyperphosphorylation.

In women, this interplay may be intensified by estrogen loss. For example, animal models of ovariectomy show increased cerebrovascular inflammation, reduced perfusion, and enhanced Aβ deposition—effects partially reversed by estrogen replacement (Hodis et al., 2016; Simpkins et al., 2009; Attems et al., 2014). These models suggest that estrogen’s protective role includes dampening the vascular contributions to AD pathology.

Vascular burden may also modulate the cognitive response to hormone therapy. Subgroup analyses from the WHIMS-MRI study revealed that older women on hormone therapy had increased WMH volume, particularly those with preexisting vascular risk factors (Coker et al., 2009). This has raised concern that in the presence of significant SVD, exogenous estrogen may exacerbate white matter injury, particularly when initiated late.

Conversely, studies in younger women with lower vascular burden suggest more neutral or even beneficial effects on brain perfusion and connectivity. These findings support a precision-medicine approach in which vascular status—assessed via imaging or biomarkers—guides HT candidacy and regimen.

It is important to recognize that vascular risk and estrogen deficiency intersect with social determinants of health, leading to disproportionate burden in Black and Hispanic women, who have higher rates of hypertension, diabetes, and stroke (Chinn et al., 2020). These populations are underrepresented in clinical trials, yet their risk profiles may make them more susceptible to both the benefits and harms of HT.

Incorporating vascular screening and risk stratification—particularly in midlife—may identify women most likely to benefit from early estrogen intervention and those in whom non-hormonal vascular risk management should take precedence.

Future prevention strategies should be individualized, not only by menopausal timing but also by risk phenotype. For example, a recently postmenopausal woman with a strong family history of AD, APOE-ε4 positivity, and minimal vascular burden may derive benefit from early transdermal estradiol, particularly if initiated within 5 years of menopause (Kantarci et al., 2016). In contrast, an older woman with metabolic syndrome, hypertension, and white matter hyperintensities may be better served by aggressive vascular risk reduction rather than hormone therapy.

This approach requires integrating biomarkers into decision-making, such as:

• Neuroimaging markers: hippocampal atrophy, cerebral perfusion, PET tau and amyloid (Coughlan et al., 2022; Coughlan et al., 2023; Coughlan et al., 2025).

Estrogen’s failure to show consistent benefit in isolation may reflect a need for combination strategies. Potential synergistic approaches include:

• HT + lifestyle intervention: Exercise, Mediterranean diet, and cognitive training may amplify HT effects on brain plasticity.

Such strategies should be tested in next-generation trials that use brain biomarkers as primary outcomes and recruit enriched populations at midlife.

For clinicians, translating this nuanced landscape into practice requires transparent, individualized risk-benefit counseling. Core principles include:

• Timing matters: Benefits are more likely when HT is initiated close to menopause onset (Hodis et al., 2016).

Hormone therapy should not be universally recommended for AD prevention, but neither should it be categorically dismissed—particularly in healthy women at midlife (Wharton et al., 2011). Reframing the conversation from binary risk to contextual, individualized potential empowers women to make informed choices.

Key directions for future investigation include:

• Large, long-duration trials of transdermal estradiol in at-risk midlife women, stratified by APOE status and vascular health

Only through such refined approaches can we resolve the longstanding ambiguity around estrogen and AD and deliver truly personalized prevention to the women most at risk.