Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer's disease

Abstract

Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women's brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer's disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women's health practices.

Keywords: Alzheimer’s disease; estrogen; hormone therapy; hormones; menopause; menstrual cycle; neuroimaging; pregnancy.

FIGURE 1

Overview of volumetric gray matter changes related to changes in estradiol levels and/or hormonal transitions. ACC, anterior cingulate cortex; PCC, posterior cingulate cortex.

FIGURE 2

Effects of menopause on brain amyloid-beta deposition. Summary of Pittsburgh compound B PET (PiB-PET) studies showing menopause status effects on Aβ deposition: (A) Statistical parametric maps showing higher PiB uptake, a marker of Aβ load, in key brain regions for AD in a group of post-menopausal and peri-menopausal women vs. age-controlled men (Z scores > 2 correspond to p < 0.001). (B) In these regions, Aβ load was associated with menopausal status, e.g., was highest post-menopause, intermediate in peri-menopause, and lowest pre-menopause (**different from men at p < 0.001). (C) Aβ deposition is progressive during the menopause transition, as evidenced in a representative case who underwent PiB-PET at baseline, when she was peri-menopausal, and 3 years later, when she was post-menopausal. Images are adapted from data presented in (A) Mosconi et al. (2021), (B) Mosconi et al. (2017), and (C) Mosconi et al. (2018b). PiB, Pittsburgh compound B; SUVR, standardized uptake value ratio.