A Review of the Role of Estrogens in Olfaction, Sleep and Glymphatic Functionality in Relation to Sex Disparity in Alzheimer's Disease

Abstract

Several risk factors contribute to the development of Alzheimer's disease (AD), including genetics, metabolic health, cardiovascular history, and diet. It has been observed that women appear to face a higher risk of developing AD. Among the various hypotheses surrounding the gender disparity in AD, one pertains to the potential neuroprotective properties of estrogen. Compared to men, women are believed to be more susceptible to neuropathology due to the significant decline in circulating estrogen levels following menopause. Studies have shown, however, that estrogen replacement therapies in post-menopausal women do not consistently reduce the risk of AD. While menopause and estrogen levels are potential factors in the elevated incidence rates of AD among women, this review highlights the possible roles estrogen has in other pathways that may also contribute to the sex disparity observed in AD such as olfaction, sleep, and glymphatic functionality.

Keywords: alzheimer’s disease; estrogen; glymphatic system; menopause; olfactory system; sex disparity; sleep.

Figure 1.

Incidence density rates of a) any dementia, b) Alzheimer’s disease, and c) non-AD dementia per 1000 person-years in Swedish men and women twins across late adulthood. Loess smoothing lines (with 95% confidence interval) were fit using nonparametric local polynomial regression fitting methods. Note: Beam, C. R., Kaneshiro, C., Jang, J. Y., Reynolds, C. A., Pedersen, N. L., & Gatz, M. (2018). Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer’s Disease. Journal of Alzheimer’s Disease, 64(4), 1077–1083. https://doi.org/10.3233/JAD-180141.

Figure 2.

Serum levels of both testosterone (T) and estradiol (E2) across the lifespan in men and women. Serum E2 levels of premenopausal women are represented as the mean of E2 measured during the different phases of the menstrual cycle; T: testosterone; E2: estradiol. Note: Decaroli, M. C., & Rochira, V. (2017). Aging and sex hormones in males. Virulence, 8(5), 545–570. https://doi.org/10.1080/21505594.2016.1259053.

Figure 3.

Chemical structures of estrogen. They exert their effects in several ways and play important roles in many biological functions including, but not limited to, in reproduction and the menstrual cycle, breast cancers, in osteoarthritis, in heart disease, in multiple sclerosis, in appetite and eating behavior, fat metabolism, schizophrenia, autoimmunity, and auditory and visual processing.

Figure 4.

Known and unknown relationships between estrogen, sleep, olfaction, and the glymphatic clearance system. Investigating other biological functions that are impacted by estrogen as well as their associations with neuropathology is warranted. This is to understand estrogen mediated neuroprotection and to determine who would best benefit from hormone replacement therapy (HRT).

Figure 5.

Theoretical graph representing proposed correlations between menopause and the onset of neuropathology that may result in AD. Higher levels of estrogen results in lower levels of human Tau and Aβ-42, highlighting potential neuroprotective properties of estrogen. Olfactory function is also expected to be unimpaired when estrogen levels are high.