Sex and the development of Alzheimer’s disease

Abstract

Men and women exhibit differences in the development and progression of Alzheimer’s disease (AD). The factors underlying the sex differences in AD are not well understood. This review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD. In women, events that decrease lifetime exposure to estrogens are generally associated with increased AD risk, whereas estrogen-based hormone therapy administered near the time of menopause may reduce AD risk. In men, estrogens do not exhibit age-related reduction and are not significantly associated with AD risk. Rather, normal age-related depletions of testosterone in plasma and brain predict enhanced vulnerability to AD. Both estrogens and androgens exert numerous protective actions in the adult brain that increase neural functioning and resilience as well as specifically attenuate multiple aspects of AD-related neuropathology. Aging diminishes the activational effects of sex hormones in sex-specific manners, which is hypothesized to contribute to the relationship between aging and AD. Sex steroid hormones may also drive sex differences in AD through their organizational effects during developmental sexual differentiation of the brain. Specifically, sex hormone actions during early development may confer inherent vulnerability of the female brain to development of AD in advanced age. The combined effects of organizational and activational effects of sex steroids yield distinct sex differences in AD pathogenesis, a significant variable that must be more rigorously considered in future research.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and the primary cause of dementia. Neuropathologically, AD is characterized primarily by the brain region-specific accumulation of both β-amyloid (Aβ) protein, which aggregates into soluble, toxic oligomers as well as extracellular deposits termed senile plaques, and hyperphosphorylated tau protein, which forms lesions called neurofibrillary tangles and neuropil threads (reviewed in Mucke and Selkoe 2012; Zempel and Mandelkow 2014). Although Aβ and tau are implicated as the primary mediators of AD-related synaptic loss and eventual neuronal death, AD neuropathology involves numerous additional components that contribute to disease progression including chronic gliosis, disrupted blood-brain-barrier, cerebrovascular amyloidosis, and white matter degeneration (reviewed in Vinters 2015). The single most significant risk factor for AD is advancing age (Launer et al. 1999), though the age-related changes that underlie this risk are poorly understood. Further, there are numerous genetic, environmental, and modifiable lifestyle factors that significantly affect AD risk (reviewed in Tanzi 2012; Xu et al. 2015). Development of effective prevention and treatment strategies for AD will require understanding how its pathogenesis is affected by the individual and interactive effects of these risk factors.

An extensive yet still woefully incomplete literature indicates that another important regulator of AD risk is sex. Developmental and physiological differences between men and women significantly contribute to the development of several neurological conditions and diseases, including multiple sclerosis, schizophrenia, depression, and autism (reviewed in Cahill 2006). Findings suggest that the vulnerability, clinical manifestation, and neuropathological progression of AD significantly differ between men and women. Initial appreciation of sex differences in AD arose from observations of a female bias in AD prevalence, with recent findings indicating that women comprise nearly two-thirds of AD patients (Hebert et al. 2013). Although most evidence suggests that the incidence of AD is similar among men and women (reviewed in Mielke et al. 2014), women appear to have a higher incidence of AD in old age (Miech et al. 2002). There are also sex differences in the time course of disease progression, which appears to be accelerated in men (Lapane et al. 2001; Stern et al. 1997). In general, women show more robust progression of mild cognitive impairment (Lin et al. 2015) and higher severity of clinical dementia (Barnes et al. 2005; Corder et al. 2004; Irvine et al. 2012) according to most studies (reviewed in Mielke et al. 2014).

Sex also affects the strength of established AD risk factors, though these differences have generally been weakly investigated. For example, the most significant genetic risk factor for late-onset AD is the ɛ4 allele of the apolipoprotein E gene (APOE4) (Saunders et al. 1993; Strittmatter et al. 1993). Notably, APOE4 is a significantly greater risk AD factor for women than men (Farrer et al. 1997; Payami et al. 1994). Similar female biases in APOE4 effects are observed in the risk of conversion from cognitively normal to mild cognitive impairment, and from mild cognitive impairment to AD (Altmann et al. 2014) as well as in cognitive dysfunction (Beydoun et al. 2012), brain atrophy (Holland et al. 2013; Liu et al. 2010), and decreased brain connectivity (Damoiseaux et al. 2012). Studies in mice have shown that APOE4 worsens cognition (Raber et al. 1998) and Aβ pathology (Cacciottolo et al. 2016) more strongly in females than males. Environmental and modifiable lifestyle risk factors of AD also are likely affected by sex. For example, sex and sex steroid hormones contribute to the relationship between obesity in midlife and the development of AD in late life (Moser and Pike 2015). Understanding how sex affects the vulnerability to and progression of AD is essential to developing effective interventions to prevent and treat the disease. In this brief review, sex differences in AD are discussed with an emphasis on the roles of sex steroid hormones, the loss of their protective effects during aging, and their organizing effects during early development.

Females, estrogens, and Alzheimer’s

Sex differences in age-related disorders are often significantly linked with the primary sex steroid hormone in women, the estrogen 17β-estradiol. As discussed below, estrogens have a wide range of beneficial actions in brain and other tissues, the loss of which may reasonably be expected to confer increased risk of AD. Consistent with this possibility, some but not all studies suggest that reductions of estrogen in adulthood are associated with increased risk of AD in women. On one hand, there is evidence that longer lifetime estrogen exposure (as indicated by larger number of reproductive years) increases dementia risk (Geerlings et al. 2001). Conversely, other studies of lifetime estrogen exposure suggest that dementia risk is associated with reduced estrogen. For example, pregnancies result in an overall decrease in women’s lifetime estrogen exposure (Bernstein et al. 1985). In comparison to nulliparous women, childbearing women exhibit increased risk for development of both cognitive impairment and dementia (Beeri et al. 2009; Colucci et al. 2006; McLay et al. 2003; Ptok et al. 2002). The relationship between low estrogen and AD risk is also supported by findings on the interactions between dementia risk and surgical menopause by oophorectomy and/or hysterectomy. Specifically, dementia risk is significantly increased by surgically induced menopause (Bove et al. 2014; Phung et al. 2010; Rocca et al. 2007; Rocca et al. 2011). Importantly, this relationship holds true only when surgical menopause is performed prior to natural menopause, thereby prematurely disrupting the normal, cyclic production of sex steroid hormones. Surgical menopause conducted after natural menopause, the timing of which would not accelerate age-related changes in sex steroid hormones, does not increase dementia risk (Imtiaz et al. 2014; Rocca et al. 2011). Reinforcing the relationship between low estrogens and AD risk are a pair of studies that compared brain levels of estrogen in aged women with and without neuropathologically diagnosed AD. In both studies, women with AD exhibited significantly reduced brain levels of the estrogens 17β-estradiol and/or estrone, an effect that appeared to be strongest in women with mean ages >80 years (Rosario et al. 2011; Yue et al. 2005). Notably, there is a clear sex difference in this relationship: no significant differences in brain levels of estrogens were observed between men with and without AD (Rosario et al. 2011). Collectively, these findings indicate a correlative relationship between low estrogen and AD, perhaps suggesting that reductions in estrogens can increase AD vulnerability specifically in women.

Although estrogen depletion in premenopausal women is a risk factor for subsequent development of AD, the efficacy of estrogen-based hormone therapy (HT) in attenuating AD risk in postmenopausal women remains uncertain. Several retrospective and prospective studies seemed to indicate a protective role of estrogen: HT users exhibited significantly reduced risk of dementia compared to non-users (Kawas et al. 1997; Paganini-Hill and Henderson 1994; Paganini-Hill and Henderson 1996; Tang et al. 1996), with increased benefits associated with prolonged use (Zandi et al. 2002). However the Women’s Health Initiative, a large double-blinded, placebo-controlled clinical trial found that HT was associated with increased risk of rather than protection from cognitive decline and dementia (Shumaker et al. 2004; Shumaker et al. 2003). Although the efficacy of HT for improving neural outcomes remains controversial, the idea of a “window of opportunity” for HT use has been suggested (Craig and Murphy 2010; Maki 2013). In brief, proponents of this position suggest that HT must be initiated near the onset of menopause rather than several years following menopause, a timing problem associated with most subjects in the Women’s Health Initiative. According to this argument, HT induces neural protection during perimenopause but these outcomes wane with advancing age and may even become deleterious in old age. A few observational studies lend support for the window of opportunity hypothesis. That is, women that began HT in midlife or within the first few years after menopause exhibited significantly reduced AD risk, whereas those that began HT in late life showed either no protection or increased risk (Henderson et al. 2005; Shao et al. 2012; Whitmer et al. 2011). Two recent clinical trials, Early versus Late Intervention Trial with Estradiol (ELITE) (Hodis et al. 2015) and Kronos Early Estrogen Prevention Study (KEEPS) (Wharton et al. 2013), have sought to evaluate the window of opportunity hypothesis by delivering HT to middle-age women near the time of menopause and assessing its effects on cognition. Data from KEEPS find no significant cognitive benefit of HT (Gleason et al. 2015); findings from ELITE have yet to be published. A clinical trial to definitively evaluate the late-life outcomes of HT administered during midlife is impractical and unlikely, thus a knowledge gap remains concerning the efficacy of HT in reducing AD risk in women. The challenge of future research is to provide insight into the potential neural efficacy of optimized HT use through appropriately designed human and animal studies.

The relationship between estrogens and AD in females has been generally well informed by experimental studies in laboratory animals. Initial work demonstrated that depletion of endogenous sex steroids in wild-type female rodents by ovariectomy (OVX) significantly increased brain levels of soluble Aβ (Petanceska et al. 2000), a finding that has since been repeated (Jayaraman et al. 2012). Similarly, OVX in various transgenic mouse models of AD results in significant acceleration of Aβ pathology and worsening of behavioral performance in comparison to gondally intact female transgenic mice (Carroll et al. 2007; Levin-Allerhand et al. 2002; Xu et al. 2002; Zhao et al. 2011; Zheng et al. 2002). Thus, as predicted by the human literature, low estrogen can create a neural environment in female rodents that promotes AD-like pathogenesis. Also in parallel to findings in humans, estrogen treatment is associated with protection against pathology. OVX non-transgenic (Jayaraman et al. 2012; Petanceska et al. 2000) and AD transgenic (Carroll et al. 2007; Levin-Allerhand et al. 2002; Xu et al. 2002; Zhao et al. 2011; Zheng et al. 2002) female rodents treated with 17β-estradiol exhibit significant lower Aβ accumulation than OVX females treated with placebo. Interestingly, in some AD transgenic strains, neither OVX nor 17β-estradiol significantly alters brain levels of Aβ (Golub et al. 2008; Green et al. 2005; Heikkinen et al. 2004). The likely reason for the discrepant findings is strain differences in neurosteroidogenesis, the brain’s inherent ability to produce 17β-estradiol and other sex steroid hormones (Charlier et al. 2015; Porcu et al. 2016). This conclusion is suggested by observations in APP23 mice, in which Aβ levels were not affected by OVX but were significantly increased by reduction of brain 17β-estradiol levels via genetic ablation of aromatase, the enzyme that generates 17β-estradiol from testosterone (Yue et al. 2005). Related findings in 3xTg-AD mice show that pharmacological inhibition of 17β-estradiol synthesis by the aromatase inhibitor anastrozole was more effective than OVX in elevating levels of Aβ in young adult females (Overk et al. 2012). Recent work has demonstrated that the protective efficacy of estrogen in non-transgenic and AD transgenic rodents is regulated by progesterone (Carroll et al. 2010b; Jayaraman et al. 2012) and may be diminished during aging (Palm et al. 2014), findings that are consistent with the window of opportunity hypothesis. Moving forward, there is a need for animal work to identify how and why aging impacts neural actions of 17β-estradiol and other sex steroids.

Males, androgens, and Alzheimer’s

In contrast to women, risk of AD in men is significantly increased by normal, age-related loss of testosterone. Most (Gillett et al. 2003; Hogervorst et al. 2003; Hogervorst et al. 2001; Paoletti et al. 2004; Watanabe et al. 2004) but not all (Pennanen et al. 2004) studies examining the relationship between AD and serum levels of testosterone report lower levels of bioavailable and/or total testosterone in men with AD. These observations suggest that, in parallel to the association between low estrogen in women and increased risk of AD, reduced testosterone levels may promote the development of AD in men. Several lines of evidence are consistent with this possibility. First, longitudinal data indicate that the relationship between low serum testosterone and AD risk is apparent at least ten years prior to the clinical diagnosis of dementia, suggesting testosterone depletion is an early component of AD risk in men (Moffat et al. 2004). Second, in comparison to neuropathologically normal men, those with both early and late stages of AD neuropathology exhibit significantly reduced brain levels of testosterone, suggesting that testosterone loss in brain occurs early in the disease process (Rosario et al. 2011; Rosario et al. 2004). This relationship appears to be sex-specific since brain levels of testosterone are not significantly different in women with AD (Rosario et al. 2011). Interestingly, in men with early AD-related pathology, brain levels of testosterone are inversely correlated with soluble Aβ (Rosario et al. 2011). Finally, a recent comparison of prostate cancer patients found that those receiving androgen deprivation therapy were significantly more likely to develop AD (Nead et al. 2016). The use of androgen deprivation therapy was previously demonstrated to increase plasma levels of Aβ (Gandy et al. 2001). Although the relationship between testosterone and AD risk remains to be completely elucidated, available evidence is most consistent with the idea that decreased testosterone in men but not women increases the development of AD.

Limited work in male rodents indicates that testosterone negatively regulates AD-related pathology. In male rats, the normal age-related decrease in brain levels of androgens significantly correlates with age-related increases in soluble Aβ (Rosario et al. 2009). Depletion of endogenous testosterone by orchiectomy (ORX) significantly increases soluble Aβ in brain (Ramsden et al. 2003). This ORX-induced increase in Aβ is reversed by the non-aromatizable androgen dihydrotestosterone but not by 17β-estradiol (Ramsden et al. 2003), suggesting that androgens are more important than estrogens for the regulation of Aβ in males. Testosterone is similarly implicated as a negative regulator of Aβ in transgenic mouse models of AD. In male 3xTg-AD mice, ORX is associated with increased Aβ accumulation in several brain regions (Rosario et al. 2010; Rosario et al. 2006), though in one study this effect failed to meet statistical significance (Overk et al. 2012). Treatment with the androgens testosterone or dihydrotestosterone significantly decreased Aβ levels in ORX 3xTg-AD mice (George et al. 2013; Rosario et al. 2010; Rosario et al. 2006). Also consistent with a protective role of testosterone is the finding that elevation of endogenous testosterone resulting from knockdown of the testosterone metabolizing enzyme aromatase results in decreased Aβ accumulation in male APP23 mice (McAllister et al. 2010). In summary, convergent findings from human and animal studies generally agree that testosterone depletion promotes development of AD. Translation of this relationship into an androgen-based intervention to prevent AD is supported by animal research but has yet to be rigorously investigated at the clinical level. A key challenge moving forward will be to determine whether testosterone-based therapy can reduce AD risk in men while avoiding the pitfalls that have plagued HT use in women.

Alzheimer’s disease and the activational effects of sex steroids

The classic view of the relationship between sex steroid hormones and AD is that the normal age-related depletion of estrogens in women and androgens in men results in a loss of neuroprotective hormone effects, which in turn might contribute to an increased risk of disease. The actions of sex steroid hormones can be broadly classified into organizational effects, which refer to the long-lasting or permanent roles of hormones in sexual differentiation and development, and activational effects, which are the more transient actions of sex hormones in the adult (Arnold and Breedlove 1985). Thus, it is the loss of activational effects of estrogens and androgens that occur as a consequence of normal aging that are thought to contribute to a spectrum of senescent changes that underlie the essential role of aging in AD pathogenesis.

Women and men exhibit qualitative differences in the age-related loss of activational effects of sex steroid hormones. This sex difference is a critical component in the relationships between sex steroids and AD. The primary factor underlying diminished activational effects of estrogens in women is the depletion of estrogen after menopause. Menopause occurs in midlife with a mean age of onset of 51 years. The losses of ovarian and menstrual cycles that characterize the menopause transition occur over a several year period and involve a variety of endocrine changes (Finch 2014; Harlow et al. 2012). The primary driving force of female reproductive senescence appears to be the exhaustion of primary follicles and oocytes, which begins in early life. Decreases in the overall number and recruitment of follicles ultimately lead to cessation of the ovarian cycle and significant reduction in estrogen production (reviewed in Finch 2014). Notably, the cyclic fluctuations in estrogen and progesterone levels that accompany normal cycles are also lost with aging, changes that may have significant consequences in tissue responses to these hormones.

In contrast to the menopause transition, male reproductive aging occurs gradually over several decades with comparatively modest age changes in sex steroid levels. Male reproductive aging, often colloquially referred to as andropause, typically begins during the fourth decade of life. It is characterized by a gradual decrease in testosterone, with total testosterone decreasing at a rate of <1% per year and bioavailable testosterone at 2–3% per year (Feldman et al. 2002; Gray et al. 1991; Muller et al. 2003). Underlying this age-related testosterone decrease are both atrophy of the testosterone-producing Leydig cells in the testes and progressive dysfunction of the hypothalamic-pituitary-gonadal axis that regulates testosterone production (reviewed in Kaufman and Vermeulen 2005). Testosterone depletion leads to a net loss in activational effects of androgens with age that increases risks of impaired function and disease in tissues throughout the body (Kaufman and Vermeulen 2005; Morley 2001) as well as increased risk of mortality (Muraleedharan and Jones 2014). Although 17β-estradiol is synthesized from testosterone, aging men do not exhibit significant decreases in plasma (Muller et al. 2003) or brain (Rosario et al. 2011; Rosario et al. 2004) levels of 17β-estradiol. Thus, decreases in sex steroid hormones and their activational effects during reproductive aging significantly vary between women and men, with distinct sex differences in the time course, the magnitude, and the identity of the sex hormones.

Brain levels of sex steroid hormones reflect not only gonadal hormone production, but also the brain’s synthesis of estrogens, androgens, and other neuroactive hormones through the process of neurosteroidogenesis (reviewed in Melcangi et al. 2008). Thus, besides menopause and andropause, age-related changes in neurosteroidogenesis are expected to significantly regulate brain levels of sex steroids. In addition to decreases in brain levels of estrone and 17β-estradiol in women and testosterone in men (Rosario et al. 2011), the AD brain exhibits decreases in a number of neurosteroids (Naylor et al. 2010; Schumacher et al. 2003; Weill-Engerer et al. 2002). It remains to be determined whether the relationship between neurosteroids and AD represent changes in pathways that contribute to AD pathogenesis or merely correlate with the disease. Expression of enzymes involved in neurosteroid synthesis also show changes in AD, including increased aromatase (Luchetti et al. 2011). Sex differences in neurosteroids in both normal and pathological aging are not well described. In male rodents, recent work indicates that normal aging is associated with decreased expression of several enzymes that contribute to testosterone synthesis (Munetomo et al. 2015), which suggests possible age-related changes in steroid synthesis. Comparison of young adult and aged non-transgenic and 3xTg-AD male mice reveals changes in levels of numerous neurosteroids by aging and or AD-related transgenes (Caruso et al. 2013). Regulation of neurosteroids may have therapeutic potential for AD as indicated by findings with the neurosteroid allopregnanolone (Irwin et al. 2011) and ligands that activate translocator protein 18kD (Barron et al. 2013), a key positive regulator of neurosteroidogenesis (reviewed in Rupprecht et al. 2010). Important knowledge gaps remain in our understanding of how aging and sex affect neurosteroidogenesis.

Estrogens, progestogens, and androgens exert a wide range of activational effects in brain that increase neural health and resistance to AD and other neurodegenerative diseases. As discussed above, estrogens and androgens directly regulate Aβ accumulation, perhaps the critical factor in AD pathogenesis (Hardy 2006; Hardy 2009). By activating cell signaling pathways that are dependent upon estrogen and androgen receptors, sex steroid hormones inhibit the production and/or enhance the degradation and clearance of Aβ (Pike et al. 2009). Similarly, sex steroids inhibit two other key components of AD pathology, tau phosphorylation and glial activation (Alvarez de la Rosa et al. 2005; Morgan and Finch 2015; Vegeto et al. 2008; Zhang et al. 2008). There are several reviews that discuss the mechanisms underlying the protective actions of sex steroids (Brinton et al. 2008; Engler-Chiurazzi et al. 2016; Pike et al. 2009; Singh and Su 2013).

Sex steroid hormones also act more generally to increase brain function and resilience. For example, estrogens and progestogens independently and interactively act on neurons and glia in the absence and presence of pathology to beneficially regulate learning and memory, neuroplasticity, and neuron survival, as already extensively reviewed (Brinton 2009; Brinton et al. 2008; De Nicola et al. 2013; Duarte-Guterman et al. 2015; Simpkins et al. 2012). Androgens also promote aspects of cognition, neuroprotection, and synaptic plasticity (Cherrier 2009; Galea 2008; MacLusky et al. 2006; Pike et al. 2008). There are a few points worth noting in the context of this discussion. First, neural effects of sex hormones often exhibit sex-specific actions. For example, hippocampal spine density in non-transgenic rodents is increased by 17β-estradiol in females (Woolley and McEwen 1992), but androgens and not 17β-estradiol increase spines in males (Leranth et al. 2003). Second, the decrease in beneficial activational effects of sex steroids involves not only decreased hormone levels, but also diminished responsiveness to at least some sex hormone actions, a concept most clearly described for estrogen (Adams et al. 2001; Bake and Sohrabji 2004; Jezierski and Sohrabji 2001; Stone et al. 2000). In rodent studies, altered neural estrogen responsiveness occurs during early reproductive senescence that is consistent in many ways with human perimenopause (Yin et al. 2015). Finally, for women, the loss of cyclic fluctuations in hormones after menopause may adversely affect interactions between estrogen and progesterone in regulation of neural outcomes. In female rodents, optimal neural effects of 17β-estradiol and progesterone are typically observed with treatment regimens that include discontinuous exposure to one or both hormones (Azcoitia et al. 1999; Barron et al. 2015; Carroll et al. 2010b; Gibbs 1996; Gibbs 2000; Jayaraman et al. 2012). In contrast, protective actions of 17β-estradiol can be attenuated by continuous co-treatment with progesterone (Carroll et al. 2007; Carroll et al. 2008; Carroll et al. 2010b; Wong et al. 2009). The numerous sex differences in age-related declines of sex hormone activational effects almost certainly contribute to sex-specific vulnerability to the development of cognitive decline and AD.

Alzheimer’s disease and the organizational effects of sex steroids

Although activational effects of sex steroid hormones are generally thought to be the primary mediator of sex differences in the development and progression of AD, emerging evidence suggests that organizational effects also play an important role. The presence of the Y chromosome, specifically the Sry gene, drives the male pattern of sexual differentiation during early development (reviewed in Morris et al. 2004). With the formation of testes, males produce testosterone that, both directly (via activation of androgen receptors) and after aromatase-mediated conversion to 17β-estradiol, mediates sexual differentiation of the brain during critical prenatal and early postnatal periods (Morris et al. 2004). Some aspects of sexual differentiation of the brain continue up through puberty (reviewed in Juraska et al. 2013). Sexual differentiation of the brain during development yields a variety of permanent structural and functional differences between the adult male and female brain (Juraska et al. 2013; Morris et al. 2004). These differences appear to include altered vulnerability to a range of neurological disorders (Cahill 2006). Thus, there is no a priori reason to assume that sex differences in AD might not result from a combination of developmental organizational effects and age-related loss of activational effects.

Comparison of sex differences in transgenic mouse models of AD supports the position that organizational effects of sex steroid hormones confer females with increased vulnerability to AD. Among the several studies that have evaluated sex differences in the levels of neuropathology in various AD transgenic models, most (Cacciottolo et al. 2016; Callahan et al. 2001; Carroll et al. 2010a; Hirata-Fukae et al. 2008; Wang et al. 2003) but not all (Clinton et al. 2007; Devi and Ohno 2015) reported significantly increased pathology in females (reviewed in Dubal et al. 2012). Importantly, neuropathology in AD transgenics typically begins in young adulthood, prior to the onset of reproductive senescence and age-related decreases in sex hormone levels and their activational effects. Thus, organizational rather than activational effects of sex hormones likely contribute to the observed sex differences. What these studies do not address is the possibility that XY chromosomal differences rather than hormone-driven sexual differentiation also contribute to sex differences in AD, a possibility that has yet to be thoroughly investigated (Dubal et al. 2012). One strategy to evaluate the role of organizational effects is by experimental manipulation of sexual differentiation. Maleness and femaleness exist along a spectrum rather than a strict binary separation (reviewed in Ainsworth 2015). The relative position along this spectrum can be altered by acutely controlling hormone exposure during critical developmental periods. Using this approach in 3xTg-AD mice, which exhibit a female bias in pathology, neonatal females were masculinized by testosterone treatment and neonatal males were feminized by pharmacological inhibition of androgen receptors (Carroll et al. 2010a). Upon reaching adulthood, the masculinized females exhibited a brain-region specific reduction in Aβ accumulation whereas the feminized males showed increased Aβ (Carroll et al. 2010a). These data suggest that developmental changes that create a relatively more feminine adult brain yield a neural environment that is more permissive to AD pathogenesis. The extent to which these findings extrapolate to humans is unknown. Collectively, these findings suggest the possibility that the female brain may be inherently more vulnerable to development of AD.

Conclusion

AD is one of several neurological diseases characterized by significant sex differences. The development of AD and its neuropathological and clinical progressions differ between men and women. Further, the penetrance of both genetic and environmental risk factors for AD can vary according to sex. These findings provide valuable opportunities to both understand the disease and develop effective and perhaps sex-specific interventions. How sex affects AD remains incompletely defined. There is compelling yet incomplete evidence that the sex-specific, age-related depletion of estrogens in women and androgens in men are significant factors in the association between age and AD. Sex steroid hormones exert a wide range of neuroprotective actions in adults, termed sex hormone activational effects, which diminish with age-related losses in hormones and hormone responsiveness. In addition, emerging evidence suggests that developmental effects of sex steroid hormones that lead to sexual differentiation of the brain, termed organizational effects, yield a female brain that may be inherently more vulnerable to AD pathogenesis. Given the importance of sex in AD, it is imperative that future research in AD not merely control for sex differences, but rather evaluate sex as an essential variable of the disease.

Significance.

The development and progression of Alzheimer’s disease are characterized by significant sex differences. Understanding the role of sex differences in Alzheimer’s disease is essential for not only identifying those most at risk but also developing interventions to prevent and treat the disease. This review highlights the roles of sex steroid hormones in this relationship, emphasizing sex differences in hormone actions and their importance during both development and aging.