on September 24, 2026
Scientific evidence from the most recent epidemiological literature shows that approximately 45% of dementias are preventable by addressing modifiable risk factors. However, clinical research has historically struggled to distinguish the impact of these factors between the sexes. Women have up to twice the risk of developing dementia compared to men, a disparity that cannot be explained solely by genetics but is rooted in profound biological, hormonal, and vascular changes.
Specific Risk Factors: Sleep, the Glymphatic System, and Cerebral Hypoxia
Alongside traditional factors, sleep and tissue oxygenation are two key elements in the female risk profile that are often underestimated. Chronic insomnia, obstructive sleep apnea, and micro-arousals disrupt the delicate mechanisms responsible for clearing waste from the nervous system.
During the first three or four hours of deep sleep (non-REM phase), the glymphatic system becomes active to remove abnormal and toxic proteins accumulated in brain tissue, such as beta-amyloid (6). However, this complex clearance system requires a trophic and well-oxygenated microenvironment to function efficiently.
In this context, chronic or intermittent cerebral hypoxia plays a major role. Some women may experience reduced oxygen supply to brain tissue due to physiological or anatomical-functional conditions—exacerbated by hormonal fluctuations, alterations in cerebral microcirculation typical of postmenopausal age, or undiagnosed sleep apnea. Hypoxia triggers a neuroinflammatory cascade and oxidative stress in neurons, impairing synaptic plasticity and accelerating the accumulation of toxic catabolites such as beta-amyloid and tau protein. Oxygen deprivation at the cellular level thus represents a primary driver of neurodegeneration, particularly insidious in the female brain during the menopausal transition.
Subjective Memory Complaint: The First Warning Sign
Neurodegenerative diseases follow a very long clinical course, preceding the onset of overt symptoms by up to twenty years. The preclinical phase is characterized by Subjective Memory Complaint (SMC), a condition in which the patient perceives a decline in their cognitive performance (difficulty remembering names or faces) despite falling within the normal range on standard neuropsychological tests.
While one-third of individuals with SMC progress to overt pathological conditions such as Alzheimer's disease, the remaining two-thirds may attribute these symptoms to reactive conditions, such as emotional or anxious stress, or transient deficits in cerebral perfusion and oxygenation. Early identification of these alterations through advanced biomarkers and instrumental assessments of vascular and oxygen supply allows for monitoring the patient's clinical trajectory and evaluating future targeted interventions, such as the correction of sleep-disordered breathing, vascular support, or the early use of innovative therapies such as monoclonal antibodies in the earliest stages of the pathological continuum (7).
The Impact of Menopause and the Role of Estrogens
The profound change in hormonal balance during menopause corresponds to a major shift in brain function. Estrogens, present since puberty, exert a powerful neuroprotective, antioxidant, and anti-inflammatory effect on the health of the female body and brain.
The protective efficacy of hormone replacement therapy (HRT) is widely debated in the literature:
· Timing of administration: An analysis of data from the Women's Health Initiative (WHI) highlights a reduction in the risk of Alzheimer's disease of between 30% and 44% in women treated early (ages 50–59) (2).
· Cognitive outcomes and brain volumes: Observational data from the EPAD database confirm that timely preventive treatment is associated with better cognitive performance and larger volumes in key brain regions in women at genetic risk (3).
· Type of treatment: Combined estrogen-progestin therapy was associated with an increased incidence of dementia and worsening verbal memory (4).
Bibliographic References
1. GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet Public Health, 2022.
2. Manson JE, et al. Menopausal hormone therapy and health outcomes during the intervention and postintervention phases of the Women’s Health Initiative randomized trials. JAMA, 2013.
3. EPAD Consortium. Observational evidence on the association of menopausal hormone therapy with cognitive outcomes and brain volumes in at-risk populations. Alzheimer's & Dementia, 2021.
4. Shumaker SA, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA, 2003.
5. Rocca WA, et al. Survival pattern after oophorectomy in premenopausal women: a population-based cohort study. The Lancet Oncology, 2006.
6. Xie L, et al. Sleep drives metabolite clearance from the adult brain. Science, 2013.
7. Jessen F, et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimer's & Dementia, 2014.
