Sex Differences in Alzheimer’s Disease: Where Do We Stand?

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that drastically compromises patients’ and relatives’ quality of life, besides being a significant economic burden to global public health. Its pathophysiology is not completely elucidated yet, hence, the current therapies are restricted to treating the symptoms. Over the years, several epidemiological studies have shown disproportionalities in AD when sex is considered, which has encouraged researchers to investigate the potentiality of sex as a risk factor. Studies in rodent models have been used to investigate mechanistic basis of sex differences in AD, as well as the development of possible new sex-specific therapeutic strategies. However, full knowledge on factors related to this sexual dimorphism remains to be unraveled. Some findings point to differences in genetic and developmental backgrounds either earlier in life or in the aging brain. Herein we summarize the multisystemic framework behind the sex differences in AD and discuss the possible mechanisms involved in these differences raised by the literature so far in an integrative perspective.

Keywords

Aging animal models hormones humans immune system oxidative stress stress

INTRODUCTION

Alzheimer’s disease (AD) causes emotional, physical, social, and financial consequences for patients and their families, and the complexity of its etiology remains to be clarified. AD is the most common form of dementia, and memory loss is the key symptom present in the patients [1]. Even though recall of facts from the remote past (long-term memory) is preserved, they cannot remember events that happened minutes before (short-term memory). In addition, with the progression of the disease, patients find difficulties in everyday life (e.g., spatial disorientation and language disorders) which can be accompanied by comorbidities such as depression, irritability, and delusions [2]. AD is an irreversible age-related disease, and its risk increases dramatically over the years [3]. According to the US Center for Disease Control and Prevention (2001), AD is the eighth leading cause of death in the United States. Studies have predicted that the AD prevalence will triple in the next 50 years to approximately 14 million Americans [4]. The number of the AD cases on the European continent is also high [5] and the total cost of care for these patients exceeds those of cancer and cardiovascular disease together [6, 7]. Worldwide, AD is the most prevalent disease among neurodegenerative disorders [8]. In 2005, 24.2 million people had dementia (70% of which were assigned to AD) and 4.6 million new cases were counted each year since then. Latin America has the third highest prevalence of AD cases (4.9%), behind North America (6.4%) and Western Europe (5.4%), and has the second highest incidence rate— 9.2 in 1000 individuals in the population [9]. In Brazil, the prevalence and incidence of dementia are similar to that reported in other countries [10 –12].

AD can arise at middle age, but usually affects people over 65 years. The early-onset familial form of AD is rare (about 4–5% of all cases), and is related to genetic heritability [13]. On the other hand, the most common late-onset form (sporadic AD) is attributed to many triggering genetic, developmental, and environmental factors. Indeed, sporadic AD has several risk factors: age, sex, family history, depression, brain injury (traumas), increased allelic frequency of apolipoprotein E (ApoE), solvent exposure, low educational levels, and genetic mutations [2]. Existing treatments are palliative; thus, studies have been focusing on possible new drugs that would reduce disease progression and delay the appearance of the symptoms. Part of the constraints in the search of significant therapeutic targets for neuroprotective actions is the lack of a complete understanding of AD pathogenesis. The deposition of Aβ peptides [14], Aβ oligomers-induced toxicity [15], tau protein hyperphosphorylation and neurofibrillary tangles (NFT) [16], mitochondrial damage, oxidative stress and metal ions deregulation [17, 18], neuropeptides unbalance [19, 20], exacerbated neuroinflammation [14], cerebral alterations in calcium signaling and glucose metabolism (for review, see [21]) are among the hypotheses that have been proposed in the last decades to explain AD pathophysiology. Figure 1 summarizes the elements involved in the AD pathophysiological mechanisms, which may or may not follow a chronological sequence. It is recognized that they interact with each other, playing specific roles in this multifactorial process that lead to a common outcome. Although all of the aforementioned hypotheses are reasonable explanations to the variety of abnormalities found in AD, more research is needed in order to stablish causal elements and their relationship with the risk factors that have been already linked to the disease.

One of the potential risk factors that has attracted attention of AD researchers is sex. The National Institute of Health Office of Research on Women’s Health recently highlighted the need for addressing sex differences in AD research [22]. Indeed, a greater investigation of AD sex differences has been observed in recent years and studies on this topic have grown. From the epidemiological perspective, there are important controversies, with data on prevalence between the sexes being more consensual than those on incidence. Although a large body of evidence shows a greater prevalence of AD in women [3 , 23–31], scientists suggest that this apparent difference is due to an indirect consequence of the greater longevity of females [3 , 33]. However, it is not fully clear whether the higher prevalence of AD in women is entirely due to their longer life expectancy, or if other factors put women at greater risk. Although there are reports arguing that the incidence of the disease is not significantly different between the sexes despite increased prevalence [34, 35], a large number of studies have shown higher incidence of AD in women. Some of them demonstrated that AD is three times more common in women than in men [2 , 37].

The fact that there are controversial epidemiologic data does not exempt the continuous research on the biological basis of sex differences in AD. Indeed, the biochemical basis for AD-related sex differences is still a gap to be unraveled [38]. The recognition of the relevance of this issue is the strengthening of the debate and the allocation of funds for studies in this theme by the Alzheimer’s Association [39]. Thus, the clinical and preclinical studies that will be discussed in the present review bring hypotheses based on a significant body of data stating that sex should be placed as a risk factor for AD predisposition, development, and resilience.

The focus of this review is to highlight the main mechanistic pathways of the sex influence on AD risk. We discuss how changes biased by sex during the development and the aging process could modulate the disease outcome. We also gather the dimorphic pathophysiological mechanisms shown by the literature in a rationale that encompasses intrinsic factors of both sexes as genetic interactions, hormone influence, and variations in sex-specific biomarkers. Our intention is to unite gaps under an alternative view without disregarding conflicting epidemiological data or controversial results from clinical and pre-clinical studies with animal models. In this context, we find it necessary to make a brief retrospective on this important scientific tool in AD research (see below). These models allow the investigation of pathophysiological mechanisms and the evaluation of potential symptomatic and neuroprotective/preventive therapies.

ADVANCES IN AD ANIMAL MODELS

The use of animal models over the years was very important for AD research. The identification of biological targets with an explicit role in the AD early stages contributes to the development of new therapeutic strategies to alleviate or prevent this neurodegenerative condition [40]. It is important to mention that the pathophysiology observed in animal models may not necessarily reproduce all clinical findings observed in patients and, although there are a wide variety of valid animal models, none of them summarizes all AD aspects [41]. In general, AD animal models comprise non-transgenic (non-Tg)–spontaneous or induced–and transgenic (Tg) models. In addition to humans, few species (dogs, cats, sheep, and nonhuman primates) spontaneously develop amyloid plaques and tauopathies (disorders related to NFT formation) associated with cognitive decline [42 –46]. There is a limitation in the use of spontaneous models for experimental research in terms of availability, costs (based on long lifetime), standard techniques, and ethical reasons [40]. Thus, similar to other areas of research, rodents are the most used animal models of AD, despite they do not spontaneously display the histopathological characteristics during aging.

The first AD-induced rodent model was based on the cholinergic hypothesis. This hypothesis suggests that the degeneration of cholinergic neurons, which protrude from the basal forebrain to the neocortex, is an early outcome of the disease [47, 48]. This approach has provided knowledge about learning and memory impairment related to cholinergic neurotransmission, and allowed the assessment of cholinomimetics and acetylcholinesterase inhibitors, the first line of drugs for AD treatment [49 –51]. Other AD-induced model comprises the intracerebral or intracerebroventricular infusions of Aβ peptides [52]. Aβ intracerebral infusions cause learning and memory deficits, as well as other behavioral changes similar to those observed in humans [53 –55]. The administration of streptozotocin (STZ) is also used to induce an AD non-Tg model [21]. STZ selectively disrupt insulin secreting cells resulting in diabetes mellitus [56]. When administered by intracerebral infusions, STZ induces dysfunctions in the brain insulin system [57], accompanied by behavioral and neurochemical alterations related to aspects of AD.

The identification of several genes and the comprehension of its role in the early-onset familial pathology enabled the production of Tg mouse and rat models for AD. The Tg-mice models were first proposed in the mid-1990s, such as the PDAPP model, followed by the Tg2576 [58] and APP23 [59] (all AβPP-based models). The discovery of mutations in PSEN genes led to the development of PSEN1 and PSEN2 Tg mouse models. Although the aforementioned Tg animals have an increase in the Aβ₄₀/Aβ₄₂ ratio, they show few cognitive abnormalities, and lack plaque formation, tau hyperphosphorylated form, and NFT [40]. Tg-mice models of tauopathy were designed to test the development of NFT, in addition to enabling the interaction between NFTs and other aspects related to AD pathology. For example, Lewis et al. [60] have shown increased formation and distribution of NFTs in brain regions vulnerable to the amyloid lesions using the JNPL3 model. P301S Tg-mice, derived from the PS19 line, overexpress the human tau gene with a 5-fold increase compared to endogenous mouse tau. P301S mice also develop synaptic deficits and microglial activation prior to neurodegeneration and NFT [61, 62]. The rTg4510 model rapidly express neuronal loss, spatial memory deficits, and NFTs at an early age [63, 64].

The triple transgenic mouse model (3xTg-AD) was developed in an attempt to overpass or refine the remaining limitations in Tg models. Mice of this Tg strain co-express the human wild-type tau isoform and both PSEN1 and AβPP Swedish double mutations because of the crossbreeding between carriers of these genotypes. Overall, these models replicate elements consistent with the amyloid cascade hypothesis, exhibiting progressive Aβ deposition, cerebral amyloid angiopathy, astrocytosis, microgliosis, hippocampal and synaptic atrophy, neurotransmission dysfunction, and cognitive impairments (for review, see [40 , 65–67]). More recently, genetic modifications with the use of viral vectors have originated several Tg-rat models in which AD-related genes are selectively expressed in brain regions relevant to the disease [68, 69]. As recently reviewed by Do Carmo and Cuello [70], the Tg-rat models are a very good alternative to mice models because of a greater genetic, physiology, and morphology similarity with humans and a better behavioral characterization.

Overall, because it encompasses a variety of the disease aspects, AD Tg models are the most widely used nowadays. Nevertheless, the high cost, the chronological mismatched neurochemical and behavioral changes, and the genetic background of the strain itself are some drawbacks for the use of Tg models, which enlighten the relevance of the research conducted with non-Tg models as well. Both models will be reviewed from the perspective of sex differences in a later section.

EVIDENCE FOR SEX DIFFERENCES IN AD

Human findings

The discrepancies observed in previously discussed epidemiological studies may be due to many factors, such as 1) different AD diagnostic criteria and criteria for excluding other types of dementia; 2) small sample size, statistical power or lack of age groups in the analysis, which could result in inaccurate estimates; 3) type of study (e.g., cross-sectional analysis, prospective or retrospective cohort); 4) cultural differences that could affect the lifestyle over the years; and 5) inclusion/exclusion criteria regarding comorbidities [33]. In a recent study, Viña and Lloret have raised the percentage of people suffering from AD in Europe stratified by age categories. They have shown that the amount of women with AD is higher in all age groups, with the exception of the 65–69 age group [17]. Moreover, epidemiological discrepancies among Europe, Asia, and North America can be attributed to social, cultural, and historical aspects [71]. In Brazil, the annual rate of mortality of people suffering from AD has been higher in women than in men in the last decade [72]. In 2010 and 2014 the Alzheimer’s Association published two alerts highlighting the disproportionate number of women who are affected and living with AD [73, 74], particularly those aged 65 years or older, who are twice as likely to have AD compared to age-matched men.

In recent years, there has been a significant advance in the search of the physiological basis for the sex differences in AD. Before discussing them, it is important to highlight the conceptual distinction between sex and gender. Sex is an essentially biological, chromosomal, hormonal trait that relates to reproductive differences between men/male and women/female. In contrast, gender refers to psychological, social, political, and cultural differences between the sexes [75, 76]. In this context, Rocca and colleagues considered three categories of factors related to sex and gender differences in the risk of developing AD. First, there are risk factors that are equally frequent in men and women but have a stronger effect on one sex, for example the APOE genotype (see below). Second, there are risk factors that have similar effect on men and women, but are culturally or socially more common in one gender (e.g., access to education and employment). Finally, there are risk factors restricted to sex (e.g., ovariectomy and abrupt hormonal loss over a period of life). Hence, multiple factors may contribute to the differential incidence and progression of AD between men and women, including sex-related (chromosomal, epigenetic, or hormonal differences) and gender-related (psychosocial and cultural differences) factors [77].

Apolipoprotein E (ApoE), involved in the cholesterol transport, favors Aβ aggregation and the enhancement of amyloid plaques [78 –81]. There are three major isoforms of the ApoE protein (ApoE2, ApoE3,and ApoE4), encoded by three alleles of the ApoE gene (E2, E3, and E4, respectively). Carriers of an E4 allele are three to four times more susceptible to AD compared to non-carriers [82, 83]. The presence of this allele decreases the age of the disease onset in a manner dependent on the number of alleles and sex [84, 85]. For example, women with one or two E4 alleles are at higher risk than men with the same genotype in the age group up to 85 years [86]. Women with E4 also show more significant changes in the connectivity pattern of the neural network [87], more presence of tauopathy [84] and a stronger association between tau and APOE [88], reduced brain metabolism and increased brain atrophy [89], and worse memory performance than men [90]. Moreover, postmortem studies showed exacerbated deposition of amyloid plaques and NFT formation in the brains of E4 allele carriers [91, 92] and the E4 effect on AD biomarkers in the cerebrospinal fluid is more pronounced in women than in men [93]. Recently, a meta-analysis study reported the age-dependency of ApoE4 as an AD risk factor for women, being restricted to an age range of 10 years [94]. Other genetic predictors have been identified as sex-specific for AD. For example, Karch & Goate reviewed 20 genetic loci on autosomal chromosomes that are linked to increased risk of AD [95] and some of them, as Serpin genes, showed stronger association with amyloidosis, especially among females [88]. However, the fully role of such genes on AD sex differences requires further research.

The ApoE E4 genotype may also interact synergistically with alcohol consumption, smoking, physical inactivity and high saturated fat intake [96, 97]. These factors can trigger metabolic syndrome, characterized by obesity, insulin resistance, hypertension, and dyslipidemia, factors that have also been associated with an increased risk of AD [98]. As mentioned, reduced cerebral glucose metabolism is common to insulin resistance (type 2 diabetes) and AD, and it has been implicated in increased Aβ deposition, tau protein hyperphosphorylation, vascular dysfunction, and inflammation [99 –101]. Thus, these interactions may explain the differential effects of ApoE between men and women, as they differ in their exposure to smoking, alcohol consumption, food preferences, and physical activity [77].

Gender-related factors as educational level can interact with the effects of ApoE E4 genotype. In fact, women carrying the E4 allele, but with early high educational level have reduced risk of dementia [102]. In addition, individuals who perform mind stimulator activities, those requiring complex interactions with data and people, have lower risk of dementia [103]. Educational level, type of occupation during working life, and cognitively stimulating leisure activities during the middle age are part of an intellectual enrichment that may delay the cognitive decline and dementia onset [104, 105]. Leisure activities throughout life, education, and mental stimulation as part of labor are primarily gender-related and historically contingent. Indeed, men historically have higher educational attainment than women, and in some regions of the world, especially in underdeveloped and developing countries, this discrepancy is still considerable [106]. Likewise, jobs that are cognitively more demanding have been historically restricted to men (e.g., directing public or private institutions, serving high-level political roles, holding high academic positions, etc.), although in a few countries this pattern has become more equal between genders [71, 107]. In this sense, the changes in social and cultural attitudes that have been occurring in many countries over the past decades may alter future projections of gender influence on AD [108].

Finally, there are some factors restricted to sex, such as ovariectomy in women, which may be associated with an increased risk of developing AD. Research has shown that women who had bilateral ovariectomy before menopause had an increased risk of cognitive decline and dementia [77]. Bove and coworkers reported the results of a cohort study on the association between surgically induced menopause, cognitive decline, and AD. Early menopause was associated with a faster decline in cognition, specifically on episodic and semantic memories, and enhanced amyloid plaques formation in AD patients. The authors also demonstrate that estrogen replacement therapy in a perimenopause stage was associated with a slower cognitive decline [109]. Thus, it is suggested that early bilateral ovariectomy in women causes an abrupt decline in estrogen levels which might mediate a chain of reactions leading to degenerative and cerebrovascular lesions. Estrogen-related factors will be further discussed in this review. Sex differences in human AD studies are corroborated by preclinical studies with animal models, as described below. In general, the human studies discuss direct (AD prevalence/incidence and ApoE genotype) and indirect (educational and hormonal status) features related to sex differences with AD (see Table 1).

Table 1

Overview of the features related to AD sexual differences in animal models and human studies

	Features	Sexual differences	References
Human studies	AD prevalence and incidence	♀ > ♂	[2 , 37]
	Susceptibility to ApoE4 genotype	♀ > ♂	[82 , 95]
	Educational enrichment	♀ < ♂	[71 , 106–108]
	Ovariectomy	Restricted to ♀	[77, 109]
Animal models	Life expectancy regardless sexual genotype	♀ > ♂	[83]
	Aging-related gene expression changes	♀ > ♂	[124]
	Susceptibility to ApoE4 genotype	♀ > ♂	[118, 119]
	AD histological hallmarks and behavioral deficits	♀ > ♂	[113–117 , 120]

>or <indicates which sex is most likely to exhibit or suffer from the listed feature.

Table 2

AD animal models that mostly considered sex as an independent factor in the experimental design

AD animal models		Sex as an independent factor	References
Transgenic	AβPP	+++	[38 , 278]
	AβPP/PSEN1	++	[112 –114]
	Tau	++	[60 , 64]
	AβPP/Tau	+	[60]
	3xTg-AD	+++	[82 , 297]
	ApoE4	++	[118, 119]
Non-transgenic	Spontaneous	–	?*
	Induced	+	[110, 111]

The signs denote the number of studies using the type of animal model mentioned. *No studies that concomitantly used both sexes in the experimental design was found.

Studies in animal models

Table 2 summarizes the variety of AD animal models that considered sex as an independent factor in the experimental design. Most animal studies that have addressed sex differences in AD used Tg models, and, to our knowledge, there are very few studies with non-Tg animals using both sexes. For example, only two studies have recently verified the influence of sex on the STZ model. Biasibetti and colleagues [110] demonstrated that the behavioral effects and changes in neurochemical markers depended on sex and were more prominent in males. Similarly, Bao et al. [111] showed that females were more resistant to the learning and memory impairment induced by STZ administration. Spatial memory was strongly affected in AβPP/PS1 Tg-females while spared in males, at all ages. The reduction of the synaptic connectivity and the high density of hypertrophic astrocytes were associated with the memory impairment [112]. Also in the AβPP/PS1 Tg model, Wang and coworkers reported significantly increased Aβ₄₀ and Aβ₄₂ levels in the brain tissue of females compared to males at 4, 12, and 17 months. Moreover, at the ages of 12 and 17 months, the load of amyloid plaques was substantially higher in females than in males (at four months of age there were no deposits). Interestingly, the animals presented differences in Aβ levels between the sexes prior to what would correspond to the menopause period in women (at the age of 4 and 12 months). In addition, the relatively unchanged proportion between Aβ species (40/42) at 12 and 17 months for both sexes indicates that sex probably affects only the AβPP overproduction but not the Aβ generation [113]. Recently, a study also showed that in AβPP/PS1 mice the Aβ₄₀ and Aβ₄₂ levels do not differ between the sexes until nine months of age. After this, there was an increase in plasma amyloid levels in females and a reduction in males [114].

Other studies with Tg mice models (APP23 [115, 116], Tg2576 [117], and AβPP/Tau [60]) observed similar patterns. These studies found that females had higher Aβ levels in several brain regions, more deposition and amyloid plaques formation, as well as a more remarkable neurodegenerative profile when compared to males of the same age [113, 117]. Raber and colleagues showed that Tg female mice expressing human ApoE4 were more susceptible to learning impairments in the water-maze test [118]. Further, Cacciottolo et al. [119] showed stronger Aβ burden in ApoE4 females than in males. Likewise, in the 3xTg-AD model, female mice exhibited pronounced impairments on learning and memory than males in the water-maze and inhibitory avoidance tasks. However, in the novel-object recognition task there were no sex differences. It is important to note that in this study, in all age groups, no significant difference in Aβ and tau levels was detected [120], contrary to what was observed in the above-mentioned studies. Regarding models of tauopathy, rTg4510 female mice have more severe spatial memory deficits associated with an increased level of hyperphosphorylated tau [64]. JNPL3 female mice exhibit faster tau pathology, and have tau overexpression two times higher than males [60]. On the other hand, mitochondrial dysfunction is greater in male P301S mice at older age [62]. Interestingly, pharmacological treatments that target anti-Aβ actions have differentiated (even opposite) effects between the sexes in Tg mice [121], which reinforces the thesis that sex has to be taken into account in the analysis of studies using AD models. Although the development of Tg models has optimized and tackled unanswered questions, some intrinsic limitations such as the higher amyloidogenesis in females can generate more variable results. Dubal et al. [122] scrutinized how surpass these limitations, and proposed guidelines to choose those that best embodies the human condition for future research.

The mechanisms underlying the sex differences in AD are not completely understood. Recently, Broestl et al. [83] designed a remarkable experiment to investigate the effects of sex chromosomes and gonads on AD pathology using an AD Tg mice model (overexpression of AβPP). Even though depletion of gonadal hormones is a key aspect of human aging, these same steroids remain relatively stable in older rodent models [122]. To overcome this limitation, the authors depleted the hormones of mice manipulated to have female sex chromosomes, but male sex organs (testicles), as well as male sex chromosomes together with female sex organs (ovaries). Mice with male genotypes died faster regardless of whether they had male or female sex organs. This outcome suggests that sex chromosomes contribute to AD-related brain disorders in AβPP mice.

Finally, Rae and Brown [123], in an extensive review, drew attention to the genotype and sex-dependent differences in lifespan, which have important implications for designing experiments using AD Tg mice models. These authors discussed the need to standardize age-related disorders in these models in order to equate each genotype and sex with different life expectancies. Indeed, the expression profile of some genes in the hippocampus revealed differences in the development of aging-related alterations between male and female brains, which may help to clarify early changes in female brains at risk for AD. For example, in female mice brains, 44.2% of the genes underwent significant change between six and nine months of age, and two thirds of them were downregulated. In contrast, in male mice brains, only 5.4% of the genes were significantly altered during the same period. In subsequent age groups, the changes in female mice brains were much smaller (10.9% from 9 to 12 months and 6.1% from 12 to 15 months) while in the male mice brains most of the changes were related to gene upregulation between 12 and 15 months. Thus, male and female mice brains seem to follow markedly different aging paths and particularly female brains undergo age-related changes much earlier than males [124].

SEX-RELATED FACTORS IN AD

Both human studies and animal models have highlighted the importance of addressing the differences between the sexes in AD pathophysiology. In general, they showed that females are more susceptible to the disease-related features (Table 1). In this respect, it is important to mention that susceptibility and vulnerability are different concepts when considering sex-specific physiological factors involved in AD (see below). According to Kottow [125], susceptibility is a feature of subjects who have a priori disadvantages and are at risk of suffering other damages. On the other hand, vulnerable subjects would not present those disadvantages, but are at risk of damage provided a certain condition affects them. In other words, knowing that susceptibility indicates a prior weakness not yet established, but with risk of development, and vulnerability refers to the weakness already present, but with less resilience, it is possible to draw a comparison between morbidity and mortality with these concepts. Indeed, mortality means the proportion of deaths among those who may die, and morbidity the proportion of ill patients among those who may become ill. Thus, the idea of vulnerability is closer to the concept of mortality, and that of susceptibility to morbidity. Taking this into account, both conditions (i.e., susceptibility and vulnerability), when expressed differentially between the sexes, may skew the course of the disease in terms of morbidity and mortality. The view of greater vulnerability of men to the disease is congruent with previous reports. For example, one of the strongest predictors for aggressive disease course and progression to death following a diagnosis of AD is male sex [122, 126]. On the other hand, men have better overall health at older ages than their female counterparts in terms of morbidity, but not mortality [127].

Otherwise, the idea of increased susceptibility to AD by females while a greater vulnerability in males is questionable since females would be more resilient in earlier stages of the disease as shown by some studies [128 –131]. Indeed, these studies show a greater resilience of females due to protection at low levels of AD pathology [131] or an advantage of cognitive reserve [128 –130]. However, the evaluation of female’s resilience using only a single cognitive demand (i.e., verbal memory) may bias the issue, especially when studies have shown there is baseline advantage of females over males in verbal memory [132], which may hinder generalizations for the pathology as a whole. Moreover, other studies counteract these data by stating that females may be more sensitive to AD-related pathological agents and experience greater and more rapid structural loss than males. Thus, males would be more resilient because they have greater cognitive reserve [71].

From another perspective, age seems to be a key part in this discussion. Fisher et al. [33] argued that imprecise timing of pre-AD diagnosis may make the definition of age-of-onset more variable. For example, women receive the diagnosis of AD later than men. Other caveat pointed by the authors is that the use of clinical diagnosis may categorize other dementia presentations incorrectly as being AD. In this respect, sex and gender factors interact with age across development to alter risk for dementia. Brain sexual dimorphism begins in pregnancy and may promote risk or resilience on the disease outcome across the lifespan. Interestingly, males have a higher potential risk for the development of other types of dementia excepting AD, such as vascular dementia, Lewy body dementia, dementia associated with Parkinson’s disease, dementia due to frontotemporal degeneration, or by multiple causes [133]. Regarding AD-type dementia, a systematic review [71] endorsed several findings that have pointed to a shorter lifespan among males [134 –140], regardless of age at diagnosis [141]. Therefore, sex differences in the clinical manifestations of the disease may vary across the cognitive diagnostic spectrum, and additional longitudinal work is needed to better understand this dynamics process [142].

Furthermore, it is difficult to conclude whether the observed sex differences is driven by differences in the AD etiology, or simply by differences in risk factors during brain aging, such as the higher proportion of comorbidities and mortality in men or greater disability but longer survival in women [135]. The overview of mechanistic processes related to aging and addressed in this section will be discussed under the integrative rationale outlined in (Fig. 2), which shows factors intrinsic to sex and involved in the relative sex susceptibility and vulnerability to AD.

Fig. 1.

Summary of Alzheimer’s disease multifactorial mechanisms.

Fig. 2.

Integrative view of the main factors involved in AD sex differences. Data reveal substantial differences in the overall age-related changes between the brains of males and females. Aging-related components as sex hormones, stress response and the immune system seem to be involved in sex-specific brain predisposition to AD. Besides genetic factors that enhance the AD susceptibility of females, developmental changes linked to sex-specific and stress hormones directly bias females to increased AD risk. The sex-biased risk for AD in which females appear to be more susceptible to the disease raises the questions: If one sex is more susceptible, is it necessarily more vulnerable? Could the intrinsic factors linked to sex from early development to the natural aging process lead to different neuropathology processes between the sexes? Susceptibility appears to be greater in females than in males and this does not appear to be age dependent. Conversely, the vulnerability to comorbidities or intrinsic AD factors seems to be age dependent. A pattern showing that females would be more vulnerable at early ages and males would be more vulnerable at more advanced stages of the disease highlights the highest mortality rate of this sex in AD.

Sex hormones

Numerous physiological and behavioral effects of estrogen (E2) have been the focus of preclinical and clinical research. The role of E2 goes far beyond the effects on sexual differentiation and reproductive function. The drastic reduction of E2 levels is a key feature of menopause, with negative consequences to the female organism, such as on bone density and cardiovascular functioning [143, 144]. The effects of E2 on these peripheral systems are well documented, as well as the important role of this hormone on the central nervous system [145 –147]. For example, as reviewed by Galea et al. [148], E2 can increase neurogenesis in several brain regions, such as the dentate gyrus in the hippocampus, which contributes to learning and memory mechanisms. In animal models, E2 has shown a neuroprotective effect by increasing dendritic spines in the hippocampus [149], LTP upregulation [150], modulation of several neurotransmitter systems [151], and decrease in cell death by modulating mitochondrial functions [152]. E2 is also responsible for increased immunocompetence in females [153, 154]. Likewise, E2 positively regulates the expression of antioxidant enzymes, as shown by increased levels of reduced glutathione [155], which could preserve the immunologic function throughout the aging process [153 , 156–158].

Paganini-Hill and Henderson [159] reported that the marked E2 decrease during menopause contribute to the AD pathogenesis. Indeed, evidence show that E2 has a beneficial role against several dysfunctional brain systems associated with AD [160, 161]. For example, E2 can reduce Aβ levels by 1) favoring the non-amyloidogenic pathway by MAPK/ERK activation and reduction of BACE levels; 2) promoting Aβ clearance by microglial phagocytosis; and 3) regulating enzymes involved in Aβ degradation such as neprilysin (NEP) [162]. E2 also prevents the neuronal loss mediated by Aβ toxicity, and activates the anti-apoptotic Bcl-2 protein at the same time it suppresses the expression of the proapoptotic isoform [163]. Moreover, E2 decreases hyperphosphorylated tau levels, and this effect depends on the activity of kinases and phosphatases, such as GSK-3β, Wnt, and PKA [164]. E2 depletion leads to Aβ accumulation in the Tg2576 mice brain, which can be reversed by hormone replacement [165]. However, ovariectomy in females did not alter Aβ brain levels, but significantly reduced AβPP levels [166]. On the other hand, although E2 treatment reduced Aβ brain levels, AβPP levels did not change in another study [167]. Together, both studies suggest that E2 possibly influence the AβPP processing, Aβ levels, or its deposition.

Several epidemiological studies and clinical trials have suggested that the E2 replacement reduces risk of AD in healthy women, delays disease onset, and improves cognitive function in women with AD [168 –173]. In addition, women with AD presented lower serum levels of E2 [172]. On the other hand, some authors have refuted the efficacy of E2 in AD patients [173 –175]. In addition, some studies have indicated that E2 replacement is not beneficial for AD, especially when the disease is already in course [176, 177]. Others have shown increased risk for cardiovascular disease, dementia, and decreased brain volume in women aged 65 to 79 years as a consequence of this replacement [178 –180].

In face of this controversy, studies need to address multiple factors that can modulate the hormonal response in AD research [176]. For example, the studies that investigated the potential neuroprotection exerted by E2 in women have led to the hypothesis that this action only occurs in the time window called perimenopause [77, 181]. Perimenopause is a natural transition towards menopause, during which there is a sharp decline of hormone levels, especially estrogen and progesterone [182, 183]. This transition is considered a critical period to the potential neuroprotective effects of E2 [184, 185]. Another inherent problem that may result in inaccuracies is the fact that there is still no appropriate model that naturally mimics human hormonal conditions (e.g., menopause; for review on caveats and alternatives, see [122]).

Moreover, the bioavailability of E2 may influence its actions on the central nervous system. A recent study by our research group using the scopolamine-induced amnesia rat model has shown that E2 administration resulted in a bimodal effect. Specifically, although the acute treatment with E2 counteracted the scopolamine-induced acquisition impairment, E2 impaired the consolidation process in female with low physiological levels of the hormone. Differences in E2 bioavailability can activate genomic and non-genomic actions during the different phases of memory (acquisition and consolidation) and the interaction between these two pathways possibly interfered with the behavioral outcome [186]. Both the long lasting genomic and the rapid non-genomic pathways participate in the activational and organizational effects of E2 on physiological and behavioral processes [187]. From this perspective, the developmental and physiological differences between sexes, particularly regarding the activational and organizational effects of the sex steroid hormones, could contribute to the sex-related AD framework. As recently reviewed by Pike [188], the sex-specific activational variations during aging, combined to differences in the sex hormones organizational actions during early development may confer inherent vulnerability to the female sex.

In addition to E2, other sex steroid hormones such as progesterone and testosterone may also be involved in the AD sex differences. For example, recent work has demonstrated that the protective efficacy of E2 in non-Tg and AD Tg rodents is regulated by progesterone [189 –191]. Progesterone have also shown neuroprotective actions against AD, such as gamma-secretase modulation [192] and increased Aβ clearance by insulin degrading enzyme [191]. In addition, studies in cell cultures, animal models, and humans have shown that progesterone also modulates tau protein phosphorylation [193]. Unlike E2, progesterone had no effect on alpha-secretase [192, 194]. However, a study showed that the administration of progesterone in ovariectomized rats induced a downregulation of beta-secretase gene expression [195]. Progesterone administration also promoted better performance in novel-object recognition and T-maze tasks in a Tg mice model of AD [196]. In this same work, progesterone administration not only significantly reduced Aβ levels, but also synergistically increased the E2 neuroprotective action. In contrast, continuous progesterone treatment did not alter Aβ levels and eventually inhibited the E2 protective effects in another study [190]. Finally, progesterone significantly attenuated oxidative damage resulting from glutamate- [197] and Aβ-induced [198] toxicity in hippocampal cell cultures. In summary, there is evidence of a role of progesterone in the neuroprotective action of sex steroids.

The aging-related loss of androgens also has consequences to the brain. In human studies, aging-related loss of androgen has been associated with increased risk of developing AD. For example, AD men have lower circulating [199, 200] and brain testosterone levels [201, 202] compared to men without AD. Brain testosterone levels were also inversely related to the Aβ levels in men who developed early-onset AD [202]. Overall, the loss of testosterone associated with aging seems to precede the AD clinical diagnosis, suggesting that androgen depletion can be a precursor event that contributes to the disease onset [202]. Moreover, low testosterone levels agreed with increased formation of the amyloid plaques [203], lower cognitive performance [200], and reduced brain metabolism [204]. Some studies have also shown that testosterone treatment improves cognitive function in men [205, 206]. In a male reproductive aging rat model, cerebral decrease of dihydrotestosterone occurred concomitantly with increasing levels of Aβ₄₀ during aging [207]. Furthermore, androgen depletion by orchiectomy significantly accelerated cognitive deficit and brain injury in 3xTg-AD mice [208]. In APP23 mice, the genetic manipulation of aromatase, resulting in increased testosterone bioavailability, led to a significant reduction of the AD pathology and consequent improvement of the cognitive function [209]. Androgens also protect the brain against a variety of AD-related insults. For example, testosterone may protect against Aβ toxicity [210 –212], oxidative stress [213], and tau protein hyperphosphorylation [214]. The neuroprotective effects of testosterone may be related to its action at the androgen receptor, or to the conversion to E2 by aromatase [213, 215].

The loss of sex steroid hormones during aging is undoubtedly one of the mechanisms related to AD sex differences. Although each sex-specific hormone has a potential neuroprotective relevance to AD risk, female hormones present a more abrupt decline and, therefore, the susceptibility to AD would be higher in women. Conversely, men would be less susceptible to the loss of estrogen-mediated neuroprotection, but they might present greater vulnerability to other AD-related factors (Fig. 2).

Cortisol/corticosterone

Long-term glucocorticoid overload during chronic stress leads to changes in the hippocampus [216, 217], including dendritic remodeling [218], LTP reduction [219, 220], increased oxidative stress [221], and reduced hippocampal volume [222]. Chronic stress also alters the dendritic morphology of the prefrontal cortex neurons [223, 224] and suppresses neurogenesis in the dentate gyrus [217, 225], and this effect increases with aging [226]. The consequences of the functional changes mentioned above result in cognitive impairment, particularly of hippocampus-dependent memories (see [227] for review) and executive functions [228].

Of note, there is an increase in cortisol levels in both plasma and cerebrospinal fluid of AD patients. This increase is positively correlated with the degree of cognitive impairment [229], but not to the co-morbid depression symptoms of the disease [230]. In addition, a longitudinal study demonstrated that stressful life-long events are associated to an earlier onset in familial AD [231]. It is noteworthy that AD patients exhibit functional alterations in the hypothalamic-pituitary-adrenal axis (HPA) [232 –234]. In addition, AD patients with high cortisol levels have worse performance in memory tasks compared to those patients with lower levels [235]. These patients are unable to adequately cease stress responses, leading to a chronic HPA axis hyperactivity and deleterious effects on the aging brain [236].

Females live longer than males in a wide variety of animal species, including humans. Behaviors like the search for food and the risk taking are rather traits of males than females in most mammals species [237], which contributes to the increased male mortality in all ages [238, 239]. As cortisol or corticosterone is inversely associated with risk behaviors [240], plasma concentrations of stress-related hormones are considerably higher in adult females than in males [241]. On the other hand, some authors have described an aging-related decrease in cortisol levels only in women [271, 272]. Similarly, 3xTg-AD female mice presented decreased corticosterone levels compared to age-matched males, while adult females of non-Tg mice had a six-fold increase in basal plasma corticosterone compared to adult males [243]. Thus, although sexual dimorphism to stress hormones is present across life, it seems to be attenuated with aging in humans and animal models.

In humans, a large meta-analysis by Otte et al. [244] showed that the effect of aging on the cortisol response to pharmacological or psychological stressors was almost three times higher in women than in men. The size effects of some studies that controlled the sex hormones variations in women (e.g., standardization of menstrual cycles, exclusion of women using oral contraceptives or hormone replacement therapy) did not differ from the size effects of those who did not. This suggests that sex hormones did not appear to alter the effect of aging on the stress response in women. In agreement with this finding, studies that examined the effect of stress on cognition in older men and women found that acute psychosocial stressors caused memory impairment only in women [245, 246]. In other words, even with the attenuation of the differences in cortisol levels across aging, the stress response still triggers more harmful effects in females. Thus, the stress response is another AD risk factor that confers greater susceptibility to this sex (Fig. 2).

In addition to cortisol response per se, the association between stress and BDNF is another mechanism by which women may be more susceptible to AD. A meta-analysis comprising intercontinental studies found that the BDNF Met66 polymorphism, linked to lower BDNF transport, was associated with AD increased risk in women, but not in men [247]. Similarly, in a study with young adults, women with the BDNF Met66 polymorphism showed an increased cortisol response to a social stressor, while the same polymorphism was associated with a decreased cortisol response in men [248]. In addition, BDNF was decreased in cortical areas of both sexes, but BDNF was downregulated in the entorhinal cortex only in females, indicating that BDNF may be a female-specific risk gene for AD [249]. In mice, stress reduces hippocampal BDNF levels in females, but not in males [250].

In animal models of AD, stress causes deficient AβPP processing, which leads to increased Aβ₄₀ and Aβ₄₂ levels in the hippocampus [251], increased tau protein phosphorylation in the hippocampus and prefrontal cortex [252], as well as enhanced cognitive impairment [253]. Interestingly, these effects occurred only in stress-susceptible animals, and not in the stress-resistant ones [254], suggesting that stress actions on the nervous system require vulnerability to these effects. Some evidence suggests that sex-biased signaling in corticotropin-releasing factor increase molecules associated with AD pathogenesis, suggesting that stress may be a risk factor especially in women [255] and female mice [256]. In addition, treatment with a synthetic glucocorticoid (dexamethasone) potentiated the disease-related damage in 3xTg-AD mice [257]. Furthermore, AD Tg mice showed HPA axis hyperactivity that was dependent on age and sex [258]. For example, Clinton et al. [120] found that 3xTg-AD nine-month-old females had higher stress-induced corticosterone response in comparison to 3xTg-AD males and to age-matched non-Tg females. This differential stress response was not apparent in fifteen-month-old animals, along with the cognitive disparity between the sexes. It is possible that cognitive sex differences in stressful tasks exist only when females have increased stress response compared to males, regardless of genotype. The authors raised the possibility of a progressive synergistic effect between increased stress response and the AD pathology [120]. A possible role for stress response in AD sex differences is illustrated in (Fig. 2). As mentioned above, the stress-related features are more likely to participate in sex differences to AD risk earlier in life than during aging, when the sex differences regarding stress response are attenuated.

The immune system also plays an important role in the relationship between stress response and aging, and thus might be an important factor to explain sex differences in AD, as illustrated in (Fig. 2). The hypercortisolemia caused by HPA hyperactivation in AD patients [259] could result in peripheral immunosuppression [260]. Furthermore, the literature indicates that the immune system in females works more efficiently and for a longer period than in males [261] and shows stronger humoral [262] and cellular responses [156]. Thus, the sexual dimorphism in the immune response indicates that females could be more resistant to infections [263, 264], and males would be more vulnerable to diseases. Particularly in AD, the systemic immune changes exhibited by immunodeficient subjects may be causally related to increased AD pathology [243]. Thus, despite females would be more susceptible to AD—due to the genetic and developmental factors described throughout this review—males could be more vulnerable due to the difference in immunocompetence.

This view is illustrated in (Fig. 2), in an attempt to integrate all the sex differences discussed above that possibly underlie the greater AD prevalence in females. In short, the exacerbated stress response (mainly earlier in life) and the sharp decline in sex hormones levels during aging render females more susceptible to AD. In parallel, the less effective immune function in males and their shorter lifespan could confer more vulnerability to this sex once they develop AD. Some authors have already strengthened this hypothesis pointing out the higher vulnerability of male immune system which results in an increased mortality in AD male mice [243] and men [265].

NEUROCHEMICAL AND MOLECULAR FACTORS

Oxidative stress

Oxidative stress and metal levels in the brain are other mechanisms closely related to AD (Fig. 1). For example, high ion metal levels in the brain such as copper (Cu^{2 +}), zinc (Zn^{2 +}) and iron (Fe^{3 +}) may facilitate Aβ precipitation [266, 267]. The catalytic activity of Aβ reduce Cu^{2 +} and Fe^{3 +} [268] and this process may be the main source of reactive oxygen species (ROS) that provoke oxidative damage and neurodegeneration in brain regions affected by AD (see [269] for review). Furthermore, abnormalities in metal homeostasis have been shown in AD brains, such as increased levels of Fe^{3 +} and Zn^{2 +} [269, 270] and decrease in Cu^{2 +} levels [271 –274]. In addition to these metals, AβPP overexpression resulted in significantly increased manganese (Mn) levels in the brain of AD Tg mice [274, 275]. Moreover, the Cu^{2 +} deficiency observed in both AD human [271 –274] and Tg mice [116 , 276] can be a direct consequence of the AβPP/Aβ overproduction [275]. Indeed, Cu^{2 +} binding Aβ domains and AβPP N-terminal region interfering in the AβPP/Aβ metabolism [275]. Thus, such deficiency could secondarily facilitate the Aβ accumulation and amyloid plaques formation [116, 276].

Interestingly, brain oxidative stress parameters in AD seem to be distinct between sexes [277, 278]. For example, Viña and Lloret [17] discuss the role of mitochondrial mechanisms on the higher incidence of AD in women. Conversely, male AD patients have a reduction of the glutathione concentration in red blood cells when compared to female AD patients as well as healthy age-matched controls. The authors suggested that a decrease in the concentration of glutathione, the major antioxidant in cells, should render men more vulnerable to AD [279]. In addition, it is possible to observe lower levels of reduced glutathione in spleen and brain cells of male mice, which indicates an increase in oxidative status in males relative to females [280].

In the same context, metal levels could be related to sex differences in AD. Studies have shown that Cu^{2 +} levels are lower in female mice, whereas cobalt (Co) levels are higher, especially in older animals [278]. Moreover, Mn levels exhibit marked sex differences with consistently higher levels in females compared to males [278]. Sex and age differences in Cu metabolism or in Cu-mediated toxicity have also been reported in rats [281 –284]. From these findings it is possible to infer that in humans there might be differences in oxidative stress related to Cu homeostasis between sexes, which could differently influence AD progress [278]. Zn^{2 +} also contributes to the Aβ aggregation, characterized by high Zn levels in amyloid plaques [285]. Lee et al. [286] showed that mice with lower expression of the Zn transporter had lower amyloid plaque formation and higher Zn levels correlated significantly with Aβ₄₀ and Aβ₄₂ levels. This work also demonstrated that the sex difference in Zn^{2 +} levels at the synapses contributes to the discrepant amyloid plaque formation in Tg2576 mice. Females expressing higher Zn transporters had more plaques compared to the age- and genotype-matched males and older females had higher Zn^{2 +} levels than age-matched males. However, animals with lower Zn transporter did not present sex differences in Aβ deposits. In another study by Lee et al. [287], changes in E2 levels affect the brain Zn^{2 +} levels in the synaptic vesicles, so that ovariectomy increased brain Zn^{2 +} levels and E2 replacement reduced those levels. In view of the evidence above, changes in Zn^{2 +} levels in senescent animals may contribute to the AD sex differences. However, they fail to explain the differences in the Aβ processing that is already evident in young animals [38]. New studies should focus on the interaction between the aging process, changes in Zn^{2 +} levels and the AD pathogenesis.

Figure 3 illustrates the suggested interactions between oxidative stress, metal alterations, and other molecular factors (see below) that may encompass a differential cascade of events associated with AD sex differences. AβPP overexpression [113], and the increased burden of amyloid plaques associated with high Zn^{2 +} levels [286], reinforce the idea of more AD susceptibility in females. Furthermore, the increased oxidative stress due to high Cu^{2 +} levels in aging male subjects [275, 278] and the reduced antioxidant levels [279, 280] emphasize the weakening of the male defense network against toxic substrates, which is accordance with the shorter lifespan in males discussed previously.

Other molecular factors

Among other possible factors that might be involved in AD sex differences there are the AMPA glutamatergic receptors and the cognate receptors of the neuronal growth factor (NGF) related to neuronal survival, such as trkA and p75 [288]. These receptors were analyzed in the nucleus basalis of healthy, mild cognitively impaired, and mild/moderate AD patients of both sexes and the results showed that they go through a sex-dependent differential shift during the progression of the disease. Patients with AD of both sexes present less high-affinity trkA receptor compared to healthy and mild cognitive impaired groups, while low-affinity p75 type is reduced only in the nucleus basalis of women with AD [288, 289]. The reduction in the number of receptors related to neuronal survival in females depicted in (Fig. 3) is in line with the idea of increased AD susceptibility of this sex. Conversely, the same proportion of the high-affinity trkA receptors in both sexes could counterbalance the greater loss of low-affinity p75 receptors in females, maintaining the neurotrophic signaling.

Fig. 3.

Schematic representation of the possible interactions between the main neurochemical and molecular factors associated with aging and AD sex differences. (1) The catalytic Aβ ability to produce Cu^{2 +} is a source of reactive oxygen species (ROS) that provoke oxidative stress and neurodegeneration (Perry et al. [269]). In aging male subjects, Cu^{2 +} levels increase Aβ aggregation and oxidative stress (Maynard et al. [275, 278]) and (2) AD male subjects have increased mitochondrial dysfunction (Dumont et al. [62]) and oxidative stress because an antioxidant levels reduction (Liu et al. [279]; Viveros et al. [280]). (3) AβPP overexpression in females (Wang et al. [113]) significantly increases Mn levels at the same time as reduce Cu^{2 +} levels (Maynard et al. [278]). Moreover, (4) amyloid plaques have high Zn^{2 +} levels and Zn^{2 +} contributes to the aggregation [286]. Lee et al. [287] showed that females have more plaques compared to the age-matched males and older females have higher Zn^{2 +} levels than males. Although (5) the supply of NGF receptors is higher in males due to more pronounced reduction in AD female subjects [288], the same proportion of the high-affinity trkA receptors in both sexes could offset the greater loss of low-affinity p75 receptors in females maintaining the neurotrophic signal. At the same time, (6) ApoD neuroprotective actions induce glial activation and scavenging properties surrounding the amyloid plaque formation [291]. The ApoD increase only in healthy aging women may be a result of the early need for their neuroprotective actions on the inflammatory response to some stressors (e.g., Aβ oligomers and fibrils initial production), but may also indicate a delayed ApoD protective response in men. Meanwhile, (7) NEP decreased more prominently in female than male transgenic mice [297], which facilitate Aβ deposition. Finally, (8) RL could also be involved in the AD sex differences with lower expression in female animals [311]. Cu^{2 +}, ion cooper; Co, cobalt; Mn, manganese; Zn^{2 +}, ion zinc; AβPP, amyloid precursor protein; Aβ, amyloid-beta peptide; ApoD, apolipoprotein D; NGF, neurotrophic growth factor; RL, reelin; NEP, neprylisin.

The apolipoprotein D (ApoD) expression is different during aging in healthy women and men, but not in AD patients, in which ApoD expression is high in both sexes [290]. For example, there is an age-related increase in ApoD expression in cells of several brain areas in healthy women (but not men), with no signs of degeneration or death. Given that ApoD neuroprotective actions induce glial activation [291] and scavenging properties against lipid oxidation products surrounding the amyloid plaque [292], this protein might be involved in AD sex differences in two possible ways. The ApoD increase only in healthy aging women may denote the early need for their neuroprotective actions against pathogenic factors (e.g. Aβ oligomers and fibrils initial production). Alternatively, there might be a delayed ApoD protective response in men, in which ApoD levels would only increase when the AD is already installed (see Fig. 3).

NEP is one of the enzymes responsible for the degradation of Aβ [293]. It is significantly reduced with aging, as previously reported in non-Tg mice [294] and AD Tg models [295, 296]. The NEP decrease in 3xTg-AD mice was more exacerbated than that found in non-Tg mice and more prominently in females [297]. In addition, ovariectomy significantly reduced the cerebral NEP activity and E2 replacement restored this activity [298], suggesting that the activity is E2-dependent. Hirata-Fukae and coworkers [297] found that 1) when mice did not display plaque formation yet, Aβ levels were not different between the sexes and 2) female plaque-bearing mice showed significantly high Aβ levels related to an enhanced BACE activity and suppressed amount of NEP. These results suggest that both the increased Aβ production and reduced degradation may contribute to the higher risk of AD in female mice (Fig. 3).

Reelin (RL) is a chemotactic glycoprotein from the extracellular matrix that is widely produced during neurodevelopment and participates in neuronal migration [299]. In the adult brain, RL plays a role in the memory and synaptic plasticity by modulation of NMDA receptor activity, enhancement of LTP [300], and stabilization of the cytoskeleton actin [301]. The RL relationship with AD involves AβPP trafficking and processing [302] and the reduction in Aβ levels is possibly related to the enhancement of the non-amyloidogenic cascade [303]. RL pathway also prevents tau hyperphosphorylation [304] and slows the fibrils formation through a direct interaction with soluble Aβ₄₂ peptides [305]. Moreover, reduced RL expression accelerates Aβ plaque formation and tau pathology in Tg AD mice [306] and cognitive decline during normal aging of rodents and primates [307]. On the other hand, in 3xTg-AD mice there was an accumulation of RL in amyloid plaques, creating a precursor condition for senile plaque deposition [307]. This finding is in agreement with the association between RL and amyloid plaques in AD double-Tg mice model [308]. Moreover, Botella-López et al. [309] have shown that cortical RL was 40% higher in AD patients compared to controls. A recent review approached these contradictory results. In the AD brain, Aβ impairs RL signaling pathway, hindering its biological activity, which would result in a compensatory increase of the RL expression [310]. Also recently, Palladino and colleagues [311] showed that the decrease of RL levels is more expressive in the hippocampus and cerebral cortex of female Tg mice (5 to 6 times compared to males). However, in spite of a downregulation of RL expression compared to males, Tg females display fewer Aβ plaques, suggesting that additional factors, other than sex and RL levels, influence the amyloidogenic pathway in this mice model [311]. Of note, a variation in the RL gene is associated with increased risk of AD in women [312]. Table 3 summarizes the possible factors involved in the AD sex differences discussed herein.

Table 3

Markers possibly related to AD sex differences. Neurochemical (oxidative stress) and molecular (receptors and proteins) factors present variations between the sexes during natural aging and the establishment of AD.

Neurochemical and molecular factors	AD-related markers	♀	♂	References
Oxidative stress	Antioxidants	+	–	[279, 280]
	[Cu]	–	+	[278]
	[Zn]	+	–
	[Co]	+	–
	[Mn]	+	–
Receptors	TrkA	–	–	[288]
	p75	–	+
	AMPA	–	+
Proteins	ApoD (no AD)	+	–	[290]
	Neprilysin	–	+	[297]
	Reelin	–	+	[311]

The positive and negative signs indicate a greater or lesser amount of the respective marker in each sex.

Autophagy and changes in white matter are also examples of mechanisms that are linked to the risk for AD. Zhou and coworkers [313] suggested a sex-specific difference in the rate of conduction along myelinated fibers and the reduction of volume of the white matter, being the females most affected. Autophagy induction is also affected by sex and data showed that females have lower basal autophagy, which may unleash greater predisposition to AD [314]. There are several other factors correlated with AD pathophysiology that were not mentioned in the present study, such as neuropeptides (e.g., somatostatin [19] and bradykinin [20]) and other hormones (e.g., luteinizing hormone [315]). However, to our knowledge, these issues have not been approached in terms of sex differences yet.

CURRENT CAVEATS AND PERSPECTIVES

The controversial clinical and epidemiological data about AD sex differences should not be interpreted as a simple product of aging or life expectancy. In other words, the literature should not ignore the pronounced sex differences throughout the brain development that are already based on a considerable body of evidence, mainly in animal models. Our attempt here was to bring together conceptual subsidies in a rationale to embrace hypotheses that would try to elucidate discrepancies between the sexes. Our point of view is in line with the conception posed by Mazure and Swendsen [316] that the AD research needs to consider sex-specific disabilities and vulnerabilities over the years and not only what brings more susceptibility to one sex compared to the other. The future AD research should discuss the sex differences in several levels of causal approaches and its interactions.

Perhaps the main difficulty in the investigation of AD sex differences is to detect the exact moment of the changes related to the disease, which could emerge in one sex and not in the other. Indeed, most human and animal studies use subjects already affected by the disease, often conducting analyses at a specific time point and disregarding the progressive feature of AD. Other drawback often found in AD research is the mismatched chronology of the neurochemical events and the emergence of the behavioral alterations. Thus, further human and animal model research should overcome these drawbacks by investing in follow-up studies of the same subject (instead of simply separating them into age groups), in addition to better refine the limitations.

On the other hand, the increase in the lifespan of people from emerging and developed countries, together with the increased survival after AD diagnosis due to the advances in treatment, make sexual variations related to the aging process more evident (e.g., ApoD-linked sex differences). Likewise, the research with animal models may vary according to the genotype and lifespan of the AD strain used, and therefore it is important to conduct the investigations with aging- and sex-matched controls, so that correlations of behavioral and physiological biomarkers can be more reliable to the human condition (as reviewed by [123]). Thus, the evaluation at various time points during the disease progression seems to be critical. More systematic and comparative investigations would enable the identification of significant changes and contribute to detect new signaling pathways and therapeutic targets.

Indeed, despite the growing incorporation of female in AD studies, mainly in Tg models, there remains a significant lack of comparative studies between the sexes. This scenario continues in part because of the underrepresentation of females in the experimental designs, which could generate an incomplete understanding of the differences in AD studies [317]. For example, there are several biomarkers known to modulate AD pathophysiology that have already been investigated in one sex (usually in males), but have not been considered potential targets for the study of AD sex differences. Scientific findings on AD sex differences indicate that females, whether human or not, are more susceptible due to some molecular factors (such as ApoE) and present early alterations related to developmental risk (such as E2 loss and higher stress response) compared to males. Awareness of these differences should encourage studies to surpass the historical disadvantage that females have in scientific reports and evaluate both sexes. Moreover, evidences also suggest that direct factors, which confer greater susceptibility, but also indirect factors that might lead to greater vulnerability to one sex are not immutable and depend on the AD course, sex-linked intrinsic factors and comorbidities. Therefore, it is important to investigate AD under the light of a sex role for its pathophysiology. This may help to overcome some gaps in the understanding of the disease and hence benefit patients and future patients of both sexes.

Finally, our review endorses Fisher and coworkers’ suggestion [33] that biological mechanisms intrinsic to sex increase the risk of developing AD, especially those involved with changes during the aging process. They also point out that comparisons of mechanisms converging or shared by both sexes should be encouraged. Future studies should not place male versus female, or highlight the advantages and disadvantages of sex in AD, but rather observe in both sexes details that drive disease control pathways more suitable for one sex. Some authors [318, 319] currently advocate the merits and future directions on the research of sex differences in AD. Among the main recommendations, studies should investigate not only factors directly related to the etiology of the disease, but also comorbidities that knowingly affect and interact with these factors. Moreover, the current and next therapeutic approaches for AD need to be continuously examined in light of the sex differences. Indeed, only recently this topic attracted attention [320] and the lack of information regarding the relationship between pharmacodynamic and pharmacokinetic properties of AD therapeutic agents and sex is worrying. Therefore, more efforts should be made to collect and report data on this issue.

Footnotes

ACKNOWLEDGMENTS

The authors are recipients of fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES – grant code 001). We also acknowledge the financial support of Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP, grant no. 2015/03354-3).

Authors’ disclosures available online ().

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