What is Perimenopause?
It kind of sneaks up on you - nothing dramatic at first, just little shifts. Periods become less predictable, focus feels a step behind, and you have less energy. Turns out, this “something feels off” phase has a name: perimenopause, and it’s a whole-body change, not just a hormonal one.
perimenopause. This is the transitional stage between regular menstrual cycles and menopause.2 Characterized by fluctuating estrogen levels and decreasing progesterone
levels, this stage may trigger inflammatory and neurological changes beyond reproductive shifts, disproportionately risking women's long-term brain health.
Image Source: WomensHealth.gov
We are going to dive into the “need-to-know” details, adverse neurological impacts, and protective interventions surrounding perimenopause.
How does Perimenopause cause Inflammation?
Perimenopause is characterized by irregular ovarian hormone production, particularly fluctuating estrogen levels. Estrogen has anti-inflammatory effects, regulating the immune system and its supporters. When estrogen levels decrease, pro-inflammatory messenger molecules in the blood increase, activating the immune system. This results in persistent, silent inflammation that can affect multiple organ systems, including the brain.5
In the central nervous system (CNS), this inflammation activates microglia. Think of microglia as the soldiers of the immune system in the CNS, protecting it from danger. This is really important; however, constant microglial activation is like guards becoming suspicious of everyone and hurting what they should be protecting. On a biochemical level, this means that they aggravate synaptic dysfunction, linking it to neurodegeneration causing neuronal injury and the accumulation of toxic proteins.6
This inflammatory response can help us understand why biological females experience greater risk of certain chronic neurodegenerative disorders. Rather than being an isolated reproductive event, perimenopause may represent a systemic biological transition with consequences for brain aging. Recognizing perimenopause as an inflammatory phase could improve early identification of increased neurological risk factors.
Fast Fact: Because of perimenopause, people with female reproductive organs are more
Image Source: Istock
How does Perimenopause impact Brain Health?
Estrogen plays a critical role in maintaining healthy brain metabolism. It supports mitochondrial energy production, glucose utilization, neuronal connections, and cerebral blood flow. During perimenopause, changes in estrogen levels may reduce the brain’s ability to efficiently generate energy, forcing neurons to rely on less effective fuel sources. This metabolic stress can contribute to memory lapse, brain fog, and reduced cognitive function. These symptoms are often seen during the menopausal transition.8
Over time, impaired energy metabolism can create the perfect environment for neurodegeneration. Research has linked falls in estrogen levels to the accumulation of misfolded proteins, oxidative damage, and mitochondrial dysfunction, all of which are characteristics of Alzheimer’s disease. ⅔ of all Alzheimer’s cases are those of the female sex. Given that the greatest risk factor for this disease is old age, people with a higher life expectancy are at greater risk of developing Alzheimer’s. Today, it is generally accepted that both life expectancy and hormonal changes are important factors in the pathology of Alzheimer’s disease.6
The same inflammatory and mitochondrial pathway changes can also risk the development of other neurodegenerative diseases, such as Parkinson’s.9 Unfortunately, symptoms emerging in midlife are often dismissed as symptoms of normal aging rather than early indicators of neurodegeneration. In fact, women are less likely to be diagnosed and more likely to be misdiagnosed due to the dismissal of female health issues by practitioners and the lack of research in women. Viewing perimenopause as a neurological transition highlights the need for earlier monitoring, cognitive screening, and preventive interventions during this critical window. 6
Things you can start now to decrease your Risk!
Although perimenopause may increase vulnerability, it also offers an opportunity for prevention. Lifestyle strategies are essential to reduce inflammation and support metabolic health, especially during midlife.
Below are a few crucial steps to optimal neurological health:
● Diets rich in omega-3 fatty acids, fiber, fruits, vegetables, and polyphenols may further protect neuronal health.7
● Sleep optimization and stress reduction are also important, as both poor sleep and chronic stress amplify inflammation.7
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Hormone therapy has received attention as a possible neuroprotective intervention.1 In medical trials, it has been used on candidates who are approaching the menopause phase. There is now evidence that suggests estrogen-based therapy may help relieve symptoms and potentially support brain metabolism.1 However, the benefits of this therapy may depend on timing, formulation, and individual risk factors, which refers to the “critical window” hypothesis. Unfortunately, hormone therapy is not universally appropriate and should be specific to patient’s needs under a clinician’s guidance.7
Supportive strategies include:
● Management of comorbidities, such as hypertension, diabetes, obesity, and depression, all of which increase the risk of dementia.
● Practising cognitive engagement activities, social connection, and continued learning may strengthen cognitive abilities later in life.4
Together, these interventions suggest that perimenopause should not only be viewed as a risk period, but also as a key stage for proactive brain health promotion.4
References
1. Barth, C., Galea, L. A. M., Jacobs, E. G., Lee, B. H., Westlye, L. T., & de Lange, A. G. (2025). Menopausal hormone therapy and the female brain: Leveraging neuroimaging and prescription registry data from the UK Biobank cohort. eLife, 13, RP99538. https://doi.org/10.7554/eLife.99538
2. Brinton, R. D., Yao, J., Yin, F., Mack, W. J., & Cadenas, E. (2015). Perimenopause as a neurological transition state. Nature reviews. Endocrinology, 11(7), 393–405. https://doi.org/10.1038/nrendo.2015.82
3. Desai, M. K., & Brinton, R. D. (2019). Autoimmune disease in women: endocrine transition and risk across the lifespan. Frontiers in Endocrinology, 10, 265. https://doi.org/10.3389/fendo.2019.00265
4. Kang, H., Ihara, E. S., Tompkins, C. J., & Lauber, M. S. (2025). Boosting Cognitive Training through Social Engagement: Impacts on Older Adults With Subjective Cognitive Decline. Sage Open Aging, 11, 30495334251366575. https://doi.org/10.1177/30495334251366575
5. McCarthy, M., & Raval, A. P. (2020). The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease. Journal of Neuroinflammation, 17(1), 317. https://doi.org/10.1186/s12974-020-01998-9
6. Mishra, A., & Brinton, R. D. (2018). Inflammation: bridging age, menopause and APOEΕ4 genotype to Alzheimer’s disease. Frontiers in Aging Neuroscience, 10, 312. https://doi.org/10.3389/fnagi.2018.00312
7. Philip, A. E., Singh, H., Nanjundiah, S. Y., Samudrala, P. C., Theunissen, W., Robinson, J., & Banerjee, I. (2025). Impact of Exercise on Perimenopausal Syndrome: A Systematic Review of Randomized Controlled Trials. Cureus, 17(3), e80862. https://doi.org/10.7759/cureus.80862
8. Rettberg, J. R., Yao, J., & Brinton, R. D. (2013). Estrogen: A master regulator of bioenergetic systems in the brain and body. Frontiers in Neuroendocrinology, 35(1), 8–30. https://doi.org/10.1016/j.yfrne.2013.08.001
9. Unda, S. R., Marciano, S., Milner, T. A., & Marongiu, R. (2022). State-of-the-art review of the clinical research on menopause and hormone replacement therapy association with Parkinson’s disease: What meta-analysis studies cannot tell us. Frontiers in Aging Neuroscience, 14, 971007. https://doi.org/10.3389/fnagi.2022.971007