A hypothesis framework linking the menopausal transition, sleep and brain waste clearance: Insights from experimental models

AI Summary

Menopausal ovarian hormone fluctuations and decline constitute a neuroendocrine transition impacting sleep, cognition and increasing neurodegenerative disease vulnerability.
Preclinical models link ovarian hormone loss to hippocampal and prefrontal cognitive deficits, sleep-wake disruption, vascular and glial dysfunction, synaptic and mitochondrial disturbances.
Altered sleep, vascular dysfunction and neuroinflammation during menopause may impair glymphatic brain waste clearance, converging to influence cognitive ageing and disease risk.

TL;DR (AI Generated)

The menopausal transition is increasingly recognized as a neuroendocrine transition with implications for brain health, sleep, cognition and vulnerability to neurodegenerative disease.

An emerging but understudied mechanism linking menopause, sleep and neurodegeneration is the glymphatic system, a sleep-dependent brain waste clearance pathway.

This review synthesises current evidence to highlight how menopause-related sleep disruption, vascular dysfunction, neuroinflammation and potential alterations in brain-waste clearance may converge to shape cognitive ageing and neurodegenerative disease risk.

Basic summary

Front Neuroendocrinol. 2026 Nov 14:101299. doi: 10.1016/j.yfrne.2026.101299. Online ahead of print.

ABSTRACT

The menopausal transition is increasingly recognized as a neuroendocrine transition with implications for brain health, sleep, cognition and vulnerability to neurodegenerative disease. Fluctuating and declining ovarian hormones coincide with sleep disruption, vasomotor symptoms, cognitive complaints, neuroinflammation and altered blood-brain barrier integrity. Current preclinical models each capture selected components of the menopause transition and provide essential mechanistic insights into the effect of ovarian hormone loss on the brain. Across these models, endocrine change is associated with impairments in hippocampal and prefrontal-dependent cognition, altered sleep-wake regulation, vascular dysfunction, glial activation, disrupted synaptic and mitochondrial homeostasis and exacerbation of Alzheimer’s and Parkinson’s disease-like pathology. An emerging but understudied mechanism linking menopause, sleep and neurodegeneration is the glymphatic system, a sleep-dependent brain waste clearance pathway. This review synthesises current evidence to highlight how menopause-related sleep disruption, vascular dysfunction, neuroinflammation and potential alterations in brain-waste clearance may converge to shape cognitive ageing and neurodegenerative disease risk.

PMID:43034023 | DOI:10.1016/j.yfrne.2026.101299

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