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

INTRODUCTION

Alzheimer’s disease (AD) and related dementias are neurodegenerative conditions common to the aging population, affecting an estimated 55 million people worldwide [1]. In the United States (US) alone, AD affects 6.5 million individuals [2], of which 2.5 million are men and 4 million are women. This means that women account for two out of every three cases of AD in the US [3]. When broken down by age, almost every group exhibits more women than men with AD [4]. Compared to men, women are on average: diagnosed later in the disease stage [5]; have increased rates of brain atrophy [6, 7]; experience faster rates of cognitive decline [7, 8]; and have a 70% higher lifetime cost of living with the disease [9]. Moreover, women account for more than 60% of caregivers for those living with AD or related dementias [10]. In recent years, growing evidence has suggested the most at-risk group for developing AD may be the roughly 1.5 million women, aged 45 to 55, undergoing the transition through menopause each year in the US [11]. Universal symptoms experienced during menopause are repeatedly and consistently being linked to poor outcomes in women’s brain health [6, 12–18], and unsurprisingly, women have a one in five lifetime risk of developing AD by age 45 as compared to a one in ten risk for age-matched men [19].

While age is the largest risk factor for developing AD, there are countless others ranging from genetic and unmodifiable (APOE4 genotype, Down syndrome, genetic mutations) to “modifiable” behavioral and environmental (smoking, physical/social/mental activity, diet, education, pollution, sleep, etc.) that have been linked with disease development and progression [2]. While most risk factors are prevalent in both men and women, decades of multidisciplinary research have shown that there are sex and gender differences within each risk category. According to Rocca et al. (2014), there are three categories that should be considered with regards to risk factors and disease: 1) factors that are present at equal frequencies in both sexes but have a greater effect in one sex over the other (e.g., APOE4 genotype); 2) factors that occur more often culturally/socially in one sex, thus having a greater effect size on one sex (e.g., low education); 3) factors that are exclusive to one sex (e.g., menopause) [20]. In addition to risk contribution, differences in presentation and response to treatments and medications in men and women are well known and documented across many diseases, and as such, it is critically important to account for these differences in AD research.

SEX AND GENDER BIAS IN MEDICAL RESEARCH

To date, the majority of medical research in animals and humans has been conducted on males, owing to the alleged difficulty in using female subjects with fluctuating hormones [21]. Indeed, changing hormone patterns across the female lifespan, menstrual cycles, pregnancy, and menopause can, and do, affect clinical outcomes and responses to therapies in regards to safety and efficacy [22]. The exclusion of female subjects in early to recent medical history has left an enormous gap in the healthcare system between men and women and has led to women being underdiagnosed and inappropriately treated in medicine [21]. Although almost 80% of drugs in the US are consumed by women, women are still being prescribed drug dosages derived from the average weight and metabolism of men, leading to increased risk of complications for women [23]. It was not until 1993 that Congress passed into law the National Institute of Health (NIH) Revitalization Act requiring women and minorities be included in clinical research [24], and not until 2014 that the NIH started requiring sex to be considered as a biological variable in preclinical research in humans and vertebrate animals [25].

While slow progress has been made (as of 2019, women account for about half of participants in clinical research funded by the NIH [26]), many areas, including brain research, are still behind. A 2020 study showed that in the three years prior to its publication date, only 52% of articles in leading neuroscience journals included female as well as male test subjects, and only 5% of studies used only females as compared to 26% that used only males [27]. When looking at AD and dementia research specifically, only one-third of participants in clinical trials are women; only 12% of the allocated NIH budget for AD and dementia is allotted to women-centric research; and as of 2019 the NIH Alzheimer’s budget equates to $24 per man and only $3 per woman [28].

Although both sex and gender can, and do, influence health and disease status in humans, the two are not interchangeable. In very simplistic terms, “sex” by definition is a biological trait encoded in DNA that characterizes differences in reproductive organs and hormones, while “gender” accounts for cultural, social, and psychological traits that differ between sexes through social context [29, 30]. Although multiple sex-and gender-related factors could conceivably make a compounding contribution to a person’s risk for developing AD, most research to date has focused on sex-related mechanisms at the hormonal and molecular level, and less on gender-related factors. Preclinical research in non-human animal models is also limited to sex specific exploration as non-human animals do not have gender. Owing to these limitations, this narrative review will focus primarily on sex differences in AD and the numerous impacts that biological sex has on the relationship between sleep disruptions and AD risk. We employed the use of PubMed to search more broadly for the three main topics “Alzheimer’s disease + sleep + sex”. This search was further refined by cross referencing each main topic with other subtopics including: hormones (estrogen, progesterone, follicle stimulating hormone, luteinizing hormone), age, menopause, amyloid, tau, and individual sleep disorders/health conditions (insomnia, sleep apnea, depression, chronic pain, etc.). Citations from manuscripts and other published works were also examined.

INTERRELATIONSHIPS BETWEEN SLEEP, SEX, AND AD

Decades of research have elucidated the complex and bidirectional relationship between sleep disruptions and AD, but how biological sex influences the genetic and molecular processes underlying the sleep-AD connection is largely unknown. There is considerable evidence that sleep disruptions may be one of many AD risk factors that occur at a higher frequency and have an overall greater effect in women as compared to men. The basis for this argument, as with most sex related discussions of health and disease, hinges on hormonal changes throughout the menopausal transition. Most hormone-based research regarding AD risk in women has been gonad-centric, focusing on the loss of circulating estradiol-17-β from the ovaries following natural or surgical (hysterectomy) menopause. Falling estrogen levels from perimenopause, menopause, and hysterectomy have been associated with cognitive decline [12], elevated AD pathology [13], and a rise in sleep disruptions [14] (Fig. 1). While unsurprising, due to the broad expression of estrogen receptors throughout memory and sleep-regulating centers of the brain [31, 32], alterations in circulating levels of gonadal steroids are not the only, or even the most, dramatic hormonal change that accompanies menopause.

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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.

Profound increases in circulating levels of pituitary gonadotropins, especially follicle stimulating hormone (FSH), are a hallmark of the menopausal transition. An increase in circulating levels of FSH is the earliest detectable hormonal alteration in the transitional period of perimenopause [33]. Throughout the transition from peri- to post-menopause, a sharp and continuous increase in FSH is inevitable, and levels of FSH remain high in the years following. Compelling studies have implicated elevated FSH levels as well as estrogen loss in menopause-related neuropathological changes including cognitive decline and AD pathology as well as sleep disruptions [34]. These neuropathological changes appear to coincide with and be exacerbated by the substantial hormonal fluctuations throughout the menopausal transition (Fig. 1).

Much like hormonal fluctuations, sleep disruptions have been identified in the preclinical stages of AD and precede cognitive impairment and AD pathology by a decade or more [35]. For those who will develop late onset AD, clinical symptoms typically appear around age 65, with pathology developing up to 20 years before clinical symptoms are present [36]. When considering both this preclinical AD window and the average age of menopausal transition between 45 and 55, it becomes evident that the two overlap substantially in middle age (Fig. 1). Accordingly, a drastic increase in sleep disruptions is seen in women as compared to age matched men during this same timeframe [37, 38]. Sleep disruption commonly exemplified in AD patients includes loss of total sleep, loss of rapid eye movement (REM) sleep, loss of non-REM (NREM) sleep, loss of deep (slow wave) sleep, as well as changes in the daily sleep-wake rhythm. Increased fragmentation of the daily sleep-wake rhythm and loss of a consolidated circadian rhythm are strong AD risk factors [39–41] that may worsen as AD progresses and may contribute to AD pathology [35]. Consequently, due to its increasingly disruptive nature for both caretakers and patients, dysregulated sleep is the primary contributing factor in placing older adults (persons aged 65+ [42, 43]) into full-time care facilities [44]. Given that both AD and sleep disturbances are more prevalent in women, it is critical to unravel the complicated and bi-directional interactions between the two. Further efforts to investigate underlying biological mechanisms driving sex differences in sleep and disease will not only serve to identify potential therapeutic targets and strategies, but also to improve the quality of women’s health throughout the lifespan.

SLEEP AND ITS ROLES IN HEALTH AND AGING

To date, every studied animal species partakes in some form of sleep, a behavior which has persisted throughout millions of years of evolution. Despite its hazards and evasive critical function, humans spend about one-third of their lives asleep [45]. Research has demonstrated that sleep is necessary for survival [46] and plays widespread regulatory roles in almost every system in the body. Obtaining an appropriate amount of sleep is a proven necessity for maintaining overall health, with brain health being no exception to this rule. Sleep enhances learning and memory [47, 48]; removes waste buildup from the brain [49–51]; improves mental health and stabilizes emotions [52]; boosts the immune system and prevents infection [53]; balances insulin and glucose levels [54] and regulates appetite [55]; maintains a healthy gut microbiome [56]; facilitates healthy growth and development [57]; aids in cellular repair [58]; lowers blood pressure [59]; and more.

Failing to acquire the necessary amount of sleep can have detrimental effects on overall health and well-being. Alarmingly, lack of sleep can not only shorten life span [60], but can also lead to: disruptions in general cognitive processes [61]; increases in psychiatric conditions including depression, anxiety and suicide [62]; weakened immune function [63, 64]; and increased risk for diseases including certain cancers [65], diabetes [66], obesity [67], hypertension [68], cardiovascular disease [69], stroke [65], congestive heart failure [70], systemic inflammation and pain [53], and cognitive diseases including AD [39, 72]. Currently, the CDC recommends a minimum of 7 hours of sleep per day for the average adult, however one-third of adults report getting less than 7 hours each night [73]. While a multitude of factors contributing to a chronic lack of sleep are modifiable, the general attributes of modern lifestyles (child-care, shift work, sleep disorders, noisy environments, artificial light exposure, stress, etc.) are not conducive to consistently obtaining adequate amounts of sleep. Compounding this issue, both sleep quantity and quality naturally change and decline with advancing age.

More than half of adults by the age of 65 will experience some form of sleep problem [74] in addition to having increased sensitivity to outside factors that can alter the normal sleep-wake cycle such as jet lag, shift work, stress hormones, noise, caffeine, medications, health problems, and psychiatric disorders [75–80]. Even without health issues, sleep quality in healthy individuals naturally declines with age starting as early as age 20 and is typically significant by age 60 [81, 82]. Throughout adulthood, reduced sleep duration and increased awakenings for longer periods of time are common, and often result in increased daytime drowsiness and napping [83].

With advancing age, it is common for changes in sleep patterns to occur [78]. While sleeping each night, humans cycle through two phases of sleep known as NREM and REM which can be distinguished based on differences in recordings of electrical activity of brain and muscle activity. NREM sleep is further subdivided into three stages (N1-N3), with N3 sleep often referred to as deep or slow wave sleep (SWS) characterized by very slow, synchronized brain waves. In REM sleep, the electrical activity recordings are indistiguishable from those of wake, but muscle tone is absent, i.e., the brain appears awake but the body is paralyzed. During a night of sleep, an individual cycles through these stages approximately 4–6 times with occassional brief awakenings between bouts (for more detailed information on sleep stages, see [84]). This pattern of progression of sleep stages throughout a sleep period is called sleep architecture. The most prominent age-related change in sleep architecture typically happens within NREM. Most older adults will experience a considerable decline in deep SWS sleep, along with a rise in the lighter sleep stages—N1 and N2 [82, 85]. Ultimately, time spent in REM decreases as well [86, 87]. All of these age related sleep changes occur in both sexes, with studies showing mixed outcomes on which sex experiences stronger age related decreases in sleep quality when measuring NREM and REM sleep [88–90].

While not a perfect model for sleep or aging, animal models have provided much insight into the basic physiological processes surrounding sleep and age (for an in depth review, see [91]). Briefly, both rats and mice experience age-related changes with sleep similar to humans including an increase in fragmented sleep patterns [92–98] and changes in distribution of sleep throughout the 24-hour day [93, 95–100]. Changes in NREM and REM sleep varied by rodent strain with some showing no change with age and some showing increases or decreases with age [93–97, 100–102]. Unlike humans, most mouse strains have been shown to have increased total sleep with age [98, 103].

SEX DIFFERENCES IN SLEEP

Many sex differences exist in both subjective and objective measurements of sleep. Subjectively, women report having poorer sleep quality compared to men [38, 104–108] and two out of every three adult women do not attain the CDC recommended 7 hours of sleep per night [73]. Chief complaints include increased instances of insomnia, more difficulty falling and staying asleep, increased awakenings at night, increased sleep disturbances due to noise, not feeling rested the following morning, and increased daytime sleepiness [109–116]. Women also may experience a greater sleep debt, or a greater discrepancy in the amount of sleep needed versus the amount of sleep acquired, as compared to men [117]. Overall, women have been shown to seek treatment for sleep problems and to use sleep medications more often than men [118, 119].

Contrary to subjective measures of sleep, objective sleep measures obtained with polysomnography—a multiparameter diagnostic laboratory sleep test that combines recording of sleep stages, eye movements, and muscle activity [120]—have typically shown that women obtain “better” sleep than men in young, middle, and old age [90, 121–123]. Young adult women have been shown to fall asleep faster and stay asleep longer than men of similar ages [38, 124]. Middle-aged women spend more time asleep and exhibit higher levels of REM sleep than middle aged men [122, 124–126]. Women across all ages have be shown to have more SWS sleep [90, 127], and more restful and stable sleep than age-matched men [128, 129]. While objective measures point to women experiencing better sleep overall, the opposing outcomes of subjective sleep studies are indicative of underlying sex-related differences in how sleep is utilized in the body across the lifespan. These discrepancies could also be attributable to experimental bias and design or other sociological factors. For example: sex differences in brain wave measurements may be due to sex differences in skull thickness [123, 131]; men and women may respond differently to study environment (i.e., hospital, laboratory, home) when it comes to polysomnography; and men and women report medical issues and seek medical intervention for sleep issues at different rates [118, 119]. Any additional or combination of these factors have the potential to heavily influence sleep study outcomes and warrant further investigation.

SLEEP AND THE INFLUENCE OF FLUCTUATING HORMONES ACROSS THE FEMALE LIFESPAN

From birth until old age, women experience more hormonal fluctuations and transitional periods than men, and it is throughout these regular hormonal cycles and transitory periods that sex differences in sleep are the most pronounced. There is a substantial amount of research demonstrating the role of gonadal hormones such as estrogen and progesterone on sleep, and, to a lesser extent, pituitary hormones such as FSH and luteinizing hormone (LH) on sleep. During periods of extreme hormonal fluctuations such as puberty, pregnancy, and the menopausal transition, sleep problems are reported at an increased frequency [112, 132–139]. The similar trajectories of changes in circulating hormone levels and changes in sleep architecture and sleep quality throughout the female lifespan suggest that sleep is influenced by reproductive hormones and that this phenomenon may contribute to the vast discrepancies that have been observed between sleep in both sexes. Unsurprisingly these fluctuations in ovarian hormones have yet again pushed women and non-human animals to the margins of sleep and circadian rhythm research. A review by Kuljis et al. (2013) found that less than 20% of rhythm studies included females [140], and a review by Gervais et al. (2017) found that only about 25% of animal studies published in the previous five years included females [91]. As sleep loss over time is a compounding issue and AD develops over a decades long timespan, it is important to understand the extent of sleep disruption throughout the lifespan. It is possible that the increased rates of sleep disruption from adolescence to old age in women contributes to their increased susceptibility to AD.

Reproductive years

During puberty, when gonadal and pituitary hormones rise to high levels inducing sexual maturity, young women are more likely to develop insomnia as compared to age-matched men [137]. After menses begins and throughout reproductive years (ages 15–44 [141]), it is common for women to experience changes in sleep architecture throughout the menstrual cycle (for details on menstrual cycle and hormones, see [142]). Studies have shown that most sleep problems occur during the luteal phase (characterized by decreasing estrogen, progesterone peaks, decreasing FSH and LH (Fig. 2)) and that these sleep problems include lower subjective sleep quality [143–146], longer times to fall asleep (i.e., increased sleep latency), less time asleep compared to the total amount of time spent in bed (i.e., lower sleep efficiency) [143, 147], less REM sleep [134, 139], less SWS [139, 148], and more daytime sleepiness [148, 149]. These sleep problems are accompanied by, and potentially worsened by elevation of core body temperature [150, 151]. Women who experience pain from premenstrual syndrome (PMS) are more likely to experience sleep disruptions including insomnia and daytime sleepiness during the luteal phase [144, 152]. It is also of note that sleep appears to be more affected in women of late reproductive age with more reports of sleep disruption in both the early follicular and luteal phase [153], and more difficulty staying asleep plus less total time asleep during the luteal phase [154].

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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.

Although laboratory animal models such as rodents have different reproductive cycles than humans, they share many characteristics and have observable sex differences in sleep patterns. Like humans, female rodents experience changes in sleep patterns across their reproductive cycles. Unlike humans, rodents have a four to five day “estrous cycle” which consists of four phases—proestrus, estrus, metestrus, and diestrus [155] (for estrous cycle and hormones, see [156] and for a summary, see Fig. 2). During proestrus, when estrogen, LH, and progesterone peak and ovulation occurs, female rodents experience the least amount of sleep, and spend most of their time awake [157–160] (Fig. 2). Both REM and NREM are lower in this phase than in any other phase [159, 161–166]. During the estrus phase when estrogen, LH, and FSH are declining and progesterone is low, mice sleep the most in comparison to any other phase [159].

SLEEP-RELATED CHANGES IN AD

It is widely accepted that sleep impacts memory and cognition, and as such it has been postulated that disturbances in sleep are a risk factor for cognitive decline and neurodegenerative diseases such as AD [203–207]. Individuals with AD frequently have disrupted sleep-wake patterns compared to cognitively normal older adults [208–210]. It is estimated that up to half of those individuals with mild cognitive impairment (MCI)—a state between normal aging and early dementia [211]—and two-thirds of those with AD suffer from dysregulated sleep [203–205, 212–214]. Common sleep problems in AD patients range from increased napping, excessive daytime sleepiness, sundowning, insomnia, sleep disordered breathing, less time spent asleep while in bed (decreased sleep efficiency), decreased total sleep, decreased SWS during NREM, and increased latency to REM sleep [215, 216]. Previously, it was thought that sleep disruptions were side effects caused by the AD process; however, mounting evidence in recent years has shown that sleep disruptions occur early in the course of the disease and probably contribute to the progression of pathological changes (Fig. 1). It is likely that a bi-directional relationship exists between the two phenomena [217].

Long before cognitive symptoms are readily noticeable, in a preclinical stage of AD that can last as long as 15–20 years, amyloid-beta (Aβ) begins to build up in the brain [36, 218]. The accumulation of Aβ is believed to be a key driver of the disease (Fig. 3). It is during this time frame that sleep problems begin to manifest and to progress alongside AD pathology [208] (Fig. 1). This hypothesis is supported by several studies. In cognitively normal individuals, a decrease in time spent asleep and an increase in the number of daytime naps has been correlated with amyloid status [219]; shorter fragments of sleep duration and overall poor sleep quality have been associated with increased amyloid pathology in specific brain regions [219–222] (Fig. 3); and individuals with increased sleep fragmentation have been shown to have a 1.5-fold increased risk of developing AD [39, 223]. Both amyloid and tau must be accounted for when considering the relationship between AD pathological changes and sleep disturbances. Tau is a well-known correlate of cognitive decline in AD [224, 225], and has also been noted as the earliest observable AD-related pathology in sleep-wake regulating brain regions [226] (Fig. 3). Changes to sleep architecture have been observed both in cognitively normal older adults and those with MCI. For example, both amyloid and tau deposition are associated with decreased SWS [227–230] and increased CSF levels of Aβ₄₂ are seen in patients with more frequent arousals during SWS [231]. It has been proposed that poor sleep quality in middle-age may be predictive of amyloid and tau burden in the brain, and thus directly tied to AD risk [232].

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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.

The specific biological mechanisms that cause changes in sleep architecture with AD are unknown, and much research has explored the relationship between amyloid and tau burden and sleep. Sleep regulates diurnal fluctuations in Aβ levels in the hippocampal interstitial fluid (ISF) of mice and the cerebrospinal fluid (CSF) of humans—soluble amyloid is high during wakefulness, and much lower during sleep [233, 234]. When healthy young adults are deprived of sleep, even for just one night, levels of soluble Aβ₃₈, Aβ₄₀, and Aβ₄₂ are significantly increased by 25–30% in the CSF, potentially due to increased overnight amyloid production when compared to control subjects [235, 236]. In contrast to the body’s lymphatic system which aids in removal of metabolic waste products, the brain has its own unique system dubbed the glymphatic system that is especially active during sleep [49–51]. During wakefulness, waste products like the AD-related proteins, amyloid and tau, accumulate in the interstitial space around brain cells [237, 238]. During sleep, pulses of CSF continuously enter the interstitial space and interchange with ISF [239]. This constant flux of CSF drives waste build-up out of the interstitial space and towards the lymphatic system to be removed from the brain and body [240, 241]. Rodent studies have shown that the interstitial space increases by more than 60% during sleep, and during this time both amyloid and tau are cleared more efficiently than during wake [49, 242].

Sleep studies in AD mouse models, despite their limitations, have proven informative in elucidating how sleep dysregulation relates to AD. For example, many mouse lines have shown that increasing AD pathology is associated with increased sleep disruption. Mouse lines with increased amyloid deposition (APP/PS1, 5xFAD, PDAPP TgCRND8, and Tg2576) have more fragmented sleep wake cycles, increased wake time, and decreased levels of both NREM sleep and REM sleep [243–248]. Conversely, APP/PS1 mice that were actively immunized against amyloid regained a normal sleep-wake cycle [243]. Mouse lines with increased tau levels have also shown disrupted sleep patterns including increased wake bout duration and decreases in both NREM and REM sleep [96, 250]. Alternatively, many studies have attempted to demonstrate the opposite by measuring the effect of sleep disruption on AD pathology. Common models of sleep disruption or deprivation in mice include: 1) the “flowerpot technique” (a method in which mice are placed on a small platform over water such that loss in muscle tone during REM sleep causes the mouse to fall into the water and wake up) [234, 251], 2) intermittent tactile stimulation [234], or 3) light-dark cycle changes that disrupt circadian rhythm [252]. These techniques are not reflective of the sleep fragmentation into shorter bouts that are seen in AD patients, and only a few studies to date have attempted to model more intermittent sleep fragmentation with either presentation of wheel running or toys and gentle tactile stimulation [253, 254]. In AD mouse models, acute sleep deprivation increases Aβ levels in the hippocampal ISF, while chronic sleep restriction accelerates amyloid plaque deposition in many brain regions [234, 255]. Studies comparing sleep fragmentation versus sleep deprivation have found enhanced amyloid deposition with the sleep fragmentation approach [253, 254]. Sleep deprivation in mice has also been found to increase tau in ISF and to accelerate tau spreading in specific brain regions [256].

AGE-RELATED SEX DIFFERENCES IN AMYLOID AND TAU

Many studies have investigated sex and gender differences in amyloid and tau pathology in individuals who are cognitively normal, and individuals with MCI or AD. Overall, women have been shown to have more global AD pathology than men [257, 258]. When looking at cognitively normal individuals ranging from middle-age to advanced age, outcomes have been mixed with some showing no difference between men and women [259–263], and others showing a greater amyloid burden in women [257, 264]. Tau pathology, including neurofibrillary tangles, as well as total and phosphorylated tau in CSF, has consistently been shown to be higher in women than in men [257, 264–269], especially in the rostral middle frontal, inferior parietal, temporal, and lateral occipital lobes [270–272]. Additionally, among cognitively normal women, tau pathology has been shown to be higher in those with greater amyloid pathology [259, 274]. In those with MCI and AD, several studies have shown higher tau in women as compared to men [258, 276]. Sex also influences the effect of APOE4 on AD pathology. Among cognitively normal older adults as well as older adults with MCI, women who carry the APOE4 allele have higher levels of phosphorylated and total tau in CSF than men, and one study found increased phosphorylated tau in women who carry the APOE4 allele in addition to higher levels of amyloid [268, 277].

Despite the mixed outcomes of measuring amyloid pathology over a wide age range or in very old adults postmortem, earlier and more dramatic changes in amyloid have been exemplified in multiple studies involving women undergoing the menopausal transition [6, 16–18]. The same trends are seen with tau. Menopause has long been hypothesized to increase the risk of AD in women [34, 279]. Symptoms during menopause are largely neurological and include disruptions in many processes regulated by estrogen, including thermoregulation, sleep and circadian rhythms, mood disorders, and cognitive decline [278]. Throughout menopause, women have increased levels of amyloid and tau, show a loss of white matter integrity and reduced grey matter volume, and exhibit decreased glucose metabolism [6, 16–18]. In all of these studies, comparisons of pre-, peri-, and post-menopausal women to age-matched men found that these pathological changes were significantly higher in post-menopausal women than in men or pre-menopausal women, while the latter two groups were not significantly different [6, 16–18]. Women who experienced menopause before age 50 had increased levels of tau [280] compared to those who underwent menopause later. Additionally, women who experienced hysterectomy before 50 years of age experienced an increased rate of cognitive decline with advancing age and exhibited greater amyloid pathology postmortem [281, 282]. Overall, the changes in these neuropathological features in menopausal women precede any clinical AD symptoms and are independent of other risk factors such as age, APOE4 status, and other comorbidities [283].

In animal models of AD, loss of circulating estradiol after ovariectomy is associated with increased levels of amyloid and decreased glucose metabolism in the brain [284, 285]. Furthermore, the concomitant increase of FSH accelerates amyloid and tau pathology and impairs cognition, while blocking FSH receptors ameliorates these disease phenotypes [34]. These findings suggest that the AD process begins earlier in women than in men, and that the menopausal transition is a critical time window when sex differences in AD may emerge, potentially putting women at an elevated risk for progression to AD [261, 283].

AD NEUROPATHOLOGY IN SLEEP/WAKE REGULATING AREAS OF THE BRAIN

Many studies have looked to pathological damage by Aβ or tau in centers of the brain that regulate the sleep-wake cycle to explain the connection between AD pathology and sleep disruption and most, if not all, of these regions show some sort of AD pathology or neuronal loss [226, 286]. Multiple regions and nuclei in the brain are responsible for maintaining states of sleep or wake including: the hypothalamus containing the suprachiasmatic nucleus (SCN), tuberomammillary nucleus (TMN), ventrolateral preoptic area (VLPO)/median preoptic area (MNPO), and orexin/hypocretin neurons; the brain stem containing the dorsal raphe nuclei (DRN), locus coeruleus (LC), pedunculopontine nucleus (PPT), and laterodorsal tegmental nucleus (LDT); the midbrain which contains the ventral tegmental area (VTA); and the basal forebrain (BF) [287] (Fig. 3). The interrelationship between these areas is complex and while each region may be involved in more than one process, the LDT, PPT, TMN, DRN, and LC are generally classified as the major “wake promoting” regions [288, 289]; and the VLPO is classified as the major “sleep promoting” region. While many other regions are involved in both sleep and wake promotion, the following section will focus on sexually dimorphic areas involved in sleep promotion (for a review on all sleep/wake promoting areas, see [287]).

The VLPO in rodents and its human homolog, the intermediate nucleus, is a major sleep promoting neural substrate that stimulates sleep and inhibits wake by releasing neurotransmitters γ-aminobutyric acid (GABA) and galanin [290]. GABA and galanin bind to receptors in the hypothalamus and brainstem and serve to dampen or inhibit the wake promoting neural circuits of the brain while promoting sleep [291]. Amyloid pathology has been found in this region of AD patients, while tau pathology has been found infrequently [292]. In older adult humans, AD was associated with decreased expression of galanin-immunoreactive neurons in the intermediate nucleus [293]. Furthermore, sleep fragmentation in subjects with or without AD was inversely associated with the number of galanin-immunoreactive neurons in the area [293]. It is interesting to note that the VLPO has been proposed to be sexually dimorphic [294]. In addition to being influenced by estrogen [158, 295] the VLPO in females also has a smaller neuronal volume, and more dramatic cell loss throughout the lifespan as compared to males [294, 296].

The hypothalamic SCN, dubbed the “master clock” of the body, synchronizes circadian rhythms with the external light-dark cycle and influences the propensity to fall asleep [297]. With normal aging, circadian rhythms are altered, often showing a reduction in amplitude, meaning the difference between the peak and trough of the 24-hour rhythm is reduced. In AD, these changes are exacerbated and sleep may become fragmented; with some patients suffering a complete loss of sleep-wake rhythms [298–300]. The SCN undergoes functional and morphological changes with age, and these changes are exacerbated in AD, where degeneration of SCN neurons may also occur [301–305]. Additionally, the SCN has been shown to be sexually dimorphic in shape (longer and thinner) in women as compared to men [304, 307]; and women with AD have been shown to have a greater loss of vasoactive intestinal peptide expressing neurons which make up the core of the SCN [308].

In addition to circadian regulation, propensity to sleep is strongly regulated by the amount of time spent awake, often referred to as “sleep pressure” or the homeostatic sleep drive [309]. Sleep pressure is mediated by the neuromodulator adenosine, a product of adenosine triphosphate degradation, which accumulates throughout the day. The more adenosine is accumulated, the greater sleep pressure will be. Throughout wake, adenosine is hypothesized to be produced and accumulate at higher levels in specific brain regions, one of which is the BF [310, 311]. In AD, the BF exhibits degeneration of cholinergic neurons, which appears to be one of the earliest pathological events of the disease [312, 313] (Fig. 3). In studies of cognitively normal, MCI and early AD patients, increases in tau pathology in the BF correlate with degree of dementia [314–316]. Additionally, loss of cholinergic neurons in this region has been associated with loss of sleep-wake regulation in AD, specifically loss of REM sleep [231, 317]. The BF is also sexually dimorphic, at least in rats, as a larger neuronal volume is found in this area in male rats compared to females, and it is influenced by estradiol [318–320].

The prefrontal cortex (PFC) plays an important role in sleep as it is one of the most common sites of origin of slow-wave activity that predominates in the deepest stage of NREM sleep [321]. With normal aging, the density of slow waves declines predominantly in frontal brain regions [322–324] and, interestingly, loss of slow wave sleep occurs early in the course of AD and contributes to its neuropathological progression [325, 326]. Amyloid aggregates in cortical regions in both cognitively normal adults and those with AD [322, 327] and its increase correlates not only with memory impairment, but with decreased slow wave activity in cognitively normal older adults [227] (Fig. 3). As the glymphatic system functions predominately during sleep, and Aβ₄₂ levels have been shown to increase with decreasing SWS, it is probable that increasing Aβ and decreasing SWS exacerbate one another in a cyclic fashion, increasing neuronal degradation in AD [328]. It is of interest to note that the PFC is sexually dimorphic during early development with larger volumes present in females than in males [329, 330].

While sexual dimorphism exists in many sleep-wake regulating areas of the brain, it is possible that sex differences in the major sleep regulating region (VLPO) in combination with sex differences in multiple sleep influencing areas (SCN, BF, and PFC) have an additive effect on sleep changes in women with age. Smaller neuronal volume, more dramatic cell loss with age and AD, influence of circulating estrogen, and variance with development all have the potential to alter biological processes including sleep as well as AD progression in women.

SEX DIFFERENCES IN APOE4 AND SLEEP

One area that is still under investigation is the relationship of apolipoprotein E (APOE) and sleep. Sex differences have been reported regarding APOE4, demonstrating that females carrying this allele are at greater risk of developing AD earlier in life, have more rapid disease progression, and have more severe cognitive decline compared to males [261, 331]. Sleep may also be influenced by APOE4 genotype, with some studies reporting a relationship between APOE4 and sleep apnea [332]. For example, studies have shown that individuals with APOE4 alleles can be at increased risk for sleep apnea [333]; individuals with both APOE4 alleles and sleep apnea may have higher rates of impaired spatial working memory [334]; and individuals with APOE4 alleles may have significantly worse sleep quality than those without [335]. These studies suggest that women may be uniquely vulnerable to the combination of sleep disorders and APOE4 genotype as a risk factor for AD.

HORMONES AND THEIR EFFECTS ON SLEEP AND AD IN WOMEN

SEX DIFFERENCES IN SLEEP DISORDERS AND THEIR ASSOCIATION WITH AD

When it comes to sleep disruption and disorders, studies have shown that there appears to be a sex bias, with women experiencing sleep disorders at a higher frequency. As sleep disorders negatively impact overall health over time, the increased prevalence of sleep disorders in women could lead to a substantial negative impact on women’s overall health, especially brain health, with age. While most sleep disorders as well as comorbidities that impair sleep occur in both sexes, women experience higher rates of insomnia [37, 457–460], depression and anxiety [461, 462], RLS [173, 464], chronic pain [465], and thyroid disorders [466], all of which have been shown to worsen with age. Obstructive sleep apnea has traditionally been regarded as a male-dominated disease; however, recent research has shown that this disease presents differently in women and as such may be underdiagnosed [467]. Additionally, sleep apnea rates rise dramatically in women after menopause, and both sleep apnea and menopause increase AD risk [393, 468]. Other than menopause, female-specific diseases, such as polycystic ovary syndrome (PCOS) that are highly prevalent yet often overlooked, have been heavily linked to sleep disorders due to their comorbidities that disrupt sleep [469]. As all these sleep disorders and associated comorbidities are indirect drivers of AD risk, their increased prevalence in women may be a contributing factor to the increased rate of AD in women (Fig. 4).

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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.

CONDITIONS WITH INCREASED PREVALENCE IN WOMEN AND THEIR RELATIONSHIP TO SLEEP AND AD

CONCLUSION

Over the past several decades it has become clear that women face increased disease risk and burden owing to inadequate attention in healthcare. This imbalance stems not only from intrinsic biological factors related to female sex, but is also a result of exclusion from research, underfunding of woman-centric research, and underdiagnosis and less than optimal treatment in medicine. With the increasing aging population, gaps in knowledge of women’s brain health are a glaring example of this shortcoming as women with AD far outnumber the men. The same hormonal fluctuations that caused women and female animals to be excluded from clinical and scientific research are proving to be highly relevant and critical in the treatment and prevention of age-related diseases.

Throughout the lifespan, girls and women experience significantly more hormonal fluctuation compared to boys and men with the onset of puberty, pregnancy, and menopause. While it is possible that hormonal fluctuation from these life events has an additive effect on disease risk for women over time, it is certain that the menopausal transition is contributing to an overall decrease in brain health for most, if not all, middle-aged women. Numerous studies have linked menopause with increased AD risk, which may help to partially explain the increased number of women with AD.

Coinciding with menopause is a drastic increase in sleep disturbances which is a known risk factor for AD. Both menopause and sleep disturbances have been shown to increase AD pathology in the brain, and both pathology and sleep disturbances may be worsened by the loss of gonadal steroids and the increase of gonadotropins during menopause. Studies have shown that women have more global amyloid and tau pathology than men and increased brain atrophy in almost all age groups, and the interaction between sex, hormones, and sleep disruption may be a contributing factor.

What’s more, women are also prone to having more subjective sleep complaints throughout the lifespan and are either more likely to suffer from sleep disorders and related conditions throughout the lifespan, or to face a drastic increase in both throughout menopause. Women are at increased risk for insomnia, RLS, thyroid disorders, chronic pain, anxiety, and depression from adolescence to late adulthood, and the risk for all these plus OSA increases throughout menopause and persists into late life. All these health conditions have in turn been shown to have a negative impact on brain health and may influence AD pathology and neurodegeneration in a bidirectional manner. What is lacking is a better understanding of what the downstream mechanisms are for these interactions at the molecular level. Partially, this is due to the complex nature of the problem, although it is also at least somewhat reflective of the lack of attention to sex differences in the biomedical literature until relatively recently. A deeper examination of these understudied processes could lead to sex and gender-based therapeutics that might bridge the gap between men and women living with AD and related dementias.