MenoBrain: A Longitudinal Investigation of Menopause and Brain Health

All women who live into midlife will transition through the menopause, a critical midlife reproductive transition accompanied by widespread physiologic change. Cohort studies have provided a broad view of changes in women’s health occurring over the menopause transition, including declines in memory. However, knowledge of the neurobiological basis for these changes is limited. These gaps in knowledge are due largely to the lack of targeted, mechanistically-rigorous longitudinal studies of women’s brain health during the menopause transition, particularly during the perimenopause, the most dynamic phase of the transition. Addressing this gap is a major priority: It is during the perimenopause that women show the major changes in sex hormones, increases in menopausal symptoms such as vasomotor symptoms (VMS) and sleep problems, deteriorations in cardiovascular health, and declines in memory performance. Critically, studies of sex differences in Alzheimer’s disease (AD) frequently implicate menopause as a key contributing factor, while acknowledging the lack of rigorous studies to support those claims. To address these gaps, building on our related studies in the postmenopause, we will recruit 224 women in the late reproductive to early menopausal transition (i.e., perimenopause) stage for two assessments over a 5-year period. At each assessment, we will conduct comprehensive assessments of brain structure and function, cognition, cardiovascular health, sex hormones, and menopausal symptoms (VMS, sleep) using state of the art 7T brain magnetic resonance imaging, peripheral vascular ultrasound imaging, mass spectrometry assessments of sex hormones, and wearable objective sleep and VMS measurements. Our primary aim is to elucidate the brain and cognitive changes that occur during the perimenopause, and the factors contributing to these changes. We hypothesize (a) Alterations in whole brain and hippocampal functional connectivity at rest and during memory tasks, and decreases in hippocampal volumes and in regional cortical thicknesses and volumes; (b) Decreases in cerebrovascular health (increases in white matter hyperintensities, in perivascular space enlargement, and in vessel tortuosity, and decreases in cerebral blood flow); and (c) Declines in verbal memory. Secondary aims will (1) Determine the role of menopausal symptoms (VMS, sleep changes), cardiovascular health, and sex hormones in these changes and (2) Test a modifying role of APOE ɛ4 genotype. This work has high public health significance, as midlife is a key window for preventive efforts to forestall adverse cognitive and brain outcomes with aging, including AD, which has no cure and disproportionately affects women.