The Neurological and Immunological Transitions of the Perimenopause: Implications for Postmenopausal Neurodegenerative Disease

Abstract

While the clinical definition of perimenopause focuses on functional changes in the reproductive system, the symptoms of perimenopause are largely neurological and immunological in nature and are observed in women globally across cultures, races, and ethnicities. Estrogen is the master regulator of the metabolic system of the female brain and body. During the perimenopausal transition, what is known as the “estrogen receptor network” is disconnected from the bioenergetic system resulting in a hypometabolic state that is associated with neurological dysfunction, which in some women may increase risk for neurodegenerative disease. Moreover, an APOE4 genotype exacerbates that bioenergetic crisis. Neurological symptoms that emerge during the perimenopause reflect the disruption in multiple estrogen-regulated systems including thermoregulation, sleep and circadian rhythms, sensory processing, affect, and multiple domains of cognitive function. Many of these symptoms are also associated with risk of Alzheimer’s disease (AD), which in women is twice as high than in men. Such elevated risk is correlated to obesity and systemic inflammation due to estrogen depletion occurring in perimenopause and menopause. Aging and neurodegenerative brains are found to be associated with chronic neuroinflammation primarily due to a dysregulation of the innate immunity, mainly driven by senescent microglia. Identifying women with metabolic or inflammatory at-risk phenotypes for late-onset AD might translate into a target population that is likely to respond to estrogen replacement therapy and adjuvant therapies that serve as metabolic regulators. Transitions of female aging involve a set of sequential, system-level adaptations. The perimenopausal transition is a critical period in the neuro-adaptive landscape of the aging brain and represents a window of opportunity for precision hormone therapeutics.