Menopausal insomnia as a modifiable node of dementia risk: Mechanistic insights and intervention strategies.

The menopausal transition is often accompanied by neuropsychiatric symptoms such as sleep disturbances, representing a modifiable window for Alzheimer's disease and related dementia (ADRD) prevention. Current preventive strategies fail to address the heterogeneity of postmenopausal cognitive trajectories, where some women exhibit rapid cognitive decline while others maintain sustained resilience over decades. This divergence suggests distinct neuroendocrine mechanisms that remain poorly understood and untargeted by current interventions. Given estrogen's fundamental role in brain function, compensatory enhancement of brain-local estrogen synthesis supports synaptic integrity and promotes resilience against neurodegeneration. Parvalbumin-positive (PV) interneurons enhance synaptic activity-dependent brain-derived estradiol (BDE2) synthesis in a sex-specific manner. Non-invasive gamma-rhythmic neuromodulation targeting PV interneurons via closed-loop protocols delivered during sleep can maximize therapeutic efficacy while minimizing off-target effects. A dual-cohort, parallel-group trial using neuronal pentraxin-2 (NPTX2) as a surrogate endpoint holds promise for assessing the efficacy of ADRD prevention and risk reduction in this high-risk population.