Search

17β-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women’s health.

Menopause has been implicated in women’s greater life-time risk for Alzheimer’s disease (AD) due to its disruptive action on multiple neurobiological mechanisms resulting in amyloid-β deposition and synaptic dysfunction.While these effects are typically attributed to declines in estradiol, mechanistic analyses implicate pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), in AD pathology. In transgenic mouse models of AD, increasing FSH and LH accelerate amyloid-β deposition, while inhibiting these hormones prevents emergence of AD lesions and neurodegeneration. Herein, we take a translational approach to show that, among midlife women at risk for AD, FSH elevations over the menopause transition are associated with higher amyloid-β burden, and both FSH and LH increases are associated with lower gray matter volume in AD-vulnerable brain regions. Results were independent of age, hormone therapy usage, and plasma estradiol levels. These findings provide novel therapeutic targets for sex-based precision medicine strategies for AD prevention.

High-density lipoproteins (HDLs) are complex, heterogenous lipoprotein particles, consisting of a large family of apolipoproteins, formed in subspecies of distinct shapes, sizes, and functions and are synthesized in both the brain and the periphery. HDL apolipoproteins are important determinants of Alzheimer’s disease (AD) pathology and vascular dementia, having both central and peripheral effects on brain amyloid-beta (Aβ) accumulation and vascular functions, however, the extent to which HDL particles (HLD-P) can exchange their protein and lipid components between the central nervous system (CNS) and the systemic circulation remains unclear. In this review, we delineate how HDL’s structure and composition enable exchange between the brain, cerebrospinal fluid (CSF) compartment, and vascular cells that ultimately affect brain amyloid metabolism and atherosclerosis. Accordingly, we then elucidate how modifications of HDL-P have diagnostic and therapeutic potential for brain vascular and neurodegenerative diseases.