The brain in transition: Perimenopause through a translational lens

Perimenopause represents a neuroendocrine transition characterized by profound hormonal variability that drives structural, functional, and molecular remodeling across the brain. This narrative review synthesizes evidence spanning molecular, cellular, and systems levels to characterize endogenous neurobiological changes that occur during this period. Structural neuroimaging consistently demonstrates regionally specific alterations in gray and white matter, including volume reductions in limbic, temporal, and frontal regions, as well as changes in white matter integrity within major association tracts. Functional imaging studies reveal stage-dependent reorganization, reflected in compensatory recruitment of prefrontal networks, reduced hippocampal activation, and decreased efficiency within limbic and memory circuits, with perfusion and connectivity patterns more strongly influenced by reproductive stage than chronological age. At the molecular level, perimenopause is marked by transcriptional, metabolic, and synaptic remodeling, including altered estrogen receptor signaling, declining bioenergetic function, and increased neuroinflammatory and glial activation markers. These convergent changes suggest a potential cascade from endocrine instability to transcriptional and metabolic dysregulation, followed by neurochemical, functional, and structural adaptations that contribute to cognitive and affective vulnerability. Collectively, findings position perimenopause as a critical inflection point in women's brain aging, a period of heightened plasticity and risk, with implications for early detection and prevention strategies aimed at preserving neural and cognitive health across midlife.