Hormone-Brain Interactions in Perimenopausal Women

The growing prevalence of Alzheimer’s disease (AD) is a public health crisis, and improved methods for assessing and interpreting functional circuitry alterations will be critical for earlier detection, vulnerable subgroup classification, and identification of new treatment targets. Over 6 million Americans are affected, with women comprising two-thirds of this burden. However, while women with AD experience a faster rate of cognitive and functional decline, the biological drivers of this sex disparity remain poorly understood. Recent studies implicate the menopause transition as a critical window of vulnerability, shaping vascular brain health and large-scale network connectivity, both of which are critical in AD pathophysiology.

The primary objective of this study is to determine how fluctuations in gonadotropin(follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex steroid (estradiol, testosterone (T), and progesterone) hormones across the menstrual cycle during the perimenopausal transition relate to neural health and functional brain network organization using longitudinal multimodal magnetic resonance imaging (MRI) across two menstrual cycles.

150 healthy perimenopausal women (ages 35-55) will undergo blood collection for a comprehensible hormonal panel, multimodal MRI acquisition, a reproductive health history questionnaire adapted from the WRAP study, and a brief cognitive screen (the Montreal Cognitive Assessment, MoCA). Participants will meet Stages of Reproductive Aging Workshop (STRAW+10) stage -1 or -2 criteria, confirming perimenopause. Each participant will complete four visits within a year of enrollment, consisting of two sessions each (capturing the early follicular and mid-luteal phases) for two menstrual cycles. Each visit will last approximately 1.5-2.5 hours.

Participants will complete cognitive and reproductive history assessments online prior to the visit. At the session, they will undergo a fasting blood draw (~10 mL at 10:30 a.m.) for hormone profiling and offered a snack, followed by an MRI session (10:30 a.m.–11:30 p.m.) including safety screening and structural and functional MRI acquisition. The second set of visits will occur within a year of enrollment and will be structurally identical to the first cycle visits to enable longitudinal assessment