Perimenopausal hormonal imbalances drive Alzheimer’s risk, plasma E2:P4 ratio a potential biomarker

Researchers from the School of Life Sciences and the Gerald Choa Neuroscience Institute at the Chinese University of Hong Kong (CUHK) have found that estradiol (E2) to progesterone (P4) (E2:P4) imbalance during perimenopause likely increases the risk of Alzheimer’s disease (AD) and AD-related dementia in women via oestrogen-related receptor alpha (ERRα) dysfunction.

The study involved analyzing human brain transcriptomic and metabolomic data from the Religious Orders Study and Rush Memory and Ageing Project (ROSMAP) cohort studies, as well as evaluating the effect of perimenopausal hormonal fluctuations on AD pathophysiology using hormonal changes simulation achieved through a 4-vinylcyclohexene diepoxide (VCD)–induced accelerated ovarian failure (AOF) model, which was employed to assess animal behaviour, metabolic reprogramming, neuronal integrity, and functional changes. These animal-model evaluations were conducted on wild-type mice, 3xTg familial AD mice, and mice with neuron-specific knockdown of ERRα in the forebrain region. [Nat Commun 2025; doi:10.1038/s41467-025-66726-4]

“In our VCD-induced AOF mouse model, the extent of neurodegeneration and functional decline in the brain strongly correlated with the E2:P4 ratio, emphasizing the intimate connection between brain health and endocrine status,” wrote the authors. “Steroid hormones such as E2 and P4 freely cross the blood-brain barrier, suggesting that their effects on the ageing brain are both direct and systemic. Importantly, our data indicated that plasma E2:P4 ratio, a surrogate marker of high E2–low P4 imbalance, could serve as a potential biomarker to identify ageing women at elevated risk of cognitive and memory decline during the perimenopausal transition.”

In the brain, E2 has neuroexcitatory effects, while P4 counteracts these effects by promoting sleep, reducing anxiety, and mitigating addictive behaviours. The researchers found that P4 appeared to modulate ERα promoter occupancy, which supports downstream cholesterol homeostasis in neurons, a critical factor for maintaining neuronal bioenergetics and functional stability. [Neuroscientist 2009;15:324-332]

Cholesterol is a critical component of neuronal physiology, and its depletion in neurons disrupts synaptic vesicle exocytosis, impairs neuronal activity, and ultimately leads to dendritic spine and synapse degeneration. The APOE4 allele, the strongest genetic risk factor for late-onset AD (LOAD), is known to have greater penetrance in females. [BMC Neurosci 2008;9(Suppl 2):S16; J Neurosci 2010;30:17068-17078; Neuron 2007;56:66-78; J Neuroendocrinol 2023;35:e13209]

The authors postulated that hormonal imbalances, particularly disruptions in E2:P4 ratio during perimenopausal state, may exacerbate neuronal cholesterol depletion and mitochondrial dysfunction, contributing to heightened biological sex–biased vulnerability to LOAD in female APOE4 carriers.

The study further demonstrated that sustained P4 supplementation, delivered via osmotic pumps for more than 60 days, provided significant neuroprotective effects through restoration of a physiological E2:P4 ratio.

“Our findings suggest that P4 supplementation therapy could address the metabolic reprogramming events in neurons caused by a higher E2–lower P4 imbalance. However, for maximum neuroprotective efficacy, such therapy must be introduced early during the onset of perimenopause,” wrote the authors.

The research team hopes that future studies on women’s health will further explore the interactions between E2 and novel synthetic progestins, as well as their impact on neuronal health, enabling optimization of hormone replacement therapy strategies and timing of natural P4 use.