Sex and Sleep Disruption as Contributing Factors in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.

Keywords: Alzheimer’s disease; hormones; menopause; sex differences; sleep; women.

Fig. 1.. Relationship between sleep, hormones, and AD pathology in women.

Estradiol levels begin to decline pre-menopause, while FSH levels begin to rise. Sleep disruptions become prominent during the menopausal transition, about the time when Aβ levels in the brain begin to increase, followed later by an increase in tau. Although some cognitive issues may start in late menopause, the majority of AD-related cognitive decline occurs post-menopausal. Created with BioRender.com.

Fig. 2. Relationship between circulating hormone levels and sleep disruptions during reproductive years in women and female rodents.

In reproductive years of women and female rodents, circulating levels of gonadal hormones (estrogen and progesterone) and gonadotropins (LH and FSH) rise and fall in accordance with the menstrual (A) and estrous (B) cycle. The majority of sleep disruptions (shown in purple shading) occur in the luteal phase for women in the menstrual cycle, and in the proestrus phase of the estrous cycle for rodents. Comparison of the two suggests that high circulating levels of LH and FSH, and rising levels of progesterone may be correlated with periods of increased sleep disruptions. Created with BioRender.com.

Fig 3.. Sleep-wake influencing brain regions and AD pathology progression.

Several major brain regions are involved in maintaining states of sleep and wake—PFC (orange), BF (yellow), hypothalamus (green), and the BS (pink). Within the hypothalamus and BS, many sleep-wake influencing nuclei have been identified and are represented as dark grey circles—VLPO/MnPO, SCN, TMN, Orexin neurons, VTA, DRN, LC, PPT, and LDT. Visualizing the progression of both Aβ and tau pathology may be useful in understanding how sleep is affected throughout the course of AD. Many of the areas/nuclei involved in maintaining states of sleep and wake are affected by both Aβ and tau pathology early on in the disease, and worsening pathology with time is often correlated with more dysregulated sleep patterns. Created with Biorender.com.

Fig. 4.. Shared characteristics between common sleep disorders and health conditions with increased prevalence in women.

All conditions have been associated with an increased AD risk, increased sleep disruptions, and decreased cognitive functions. They are all increased in prevalence or severity with age, especially throughout the menopausal condition. Additionally, each condition shares many overlapping symptoms, comorbidities, and pathology with AD. Created with BioRender.com.