Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer’s Disease in Females

Evolution of locus coeruleus involvement in AD

The locus coeruleus (LC) (Fig. 1) has become the focus of numerous investigations due to its influential functions throughout the brain (Box 1) and its role as the earliest host of AD pathology [1, 2]. Renowned discoveries by Braak and colleagues have identified intraneuronal abnormal tau in the human LC prior to LC neuronal loss and subsequent LC neuronal death as tau burden increases [3, 4]; this research has since been validated in a more recent rat model [5]. Consequently, the presence and aggregation of extracellular amyloid-β protein (Aβ) in the human LC has been shown to accompany neurofibrillary tangles in the late-stage processes of Braak and Braak (BB), particularly stages V and VI [3, 4]. Moreover, the afferent and efferent projections of human LC neurons are thin, vastly arborized, and poorly myelinated, causing them to be eminently fragile [6]. This is particularly significant regarding the afferent nerve fibers that permeate through the gut to the vagus nerve and central nervous system (CNS) microvasculature; this causes the LC-NA system to be particularly vulnerable to being exposed to harmful metabolites, pathogens, and viruses [7]. These noxious microorganisms can then intensify tau hyperphosphorylation, each of which can be transmitted throughout the brain, not only degrading the LC-NA pathway but also causing detrimental alterations of more extensive neuronal function. Surviving LC neurons containing abnormal pathologies spread trans-synaptically to other brain regions exacerbating synaptic dysfunction, resulting in cognitive decline and memory impairment, and neurodegeneration [7–10]. These pathological changes can also depress neurovascular coupling and increase inflammation and blood-brain barrier (BBB) permeability [2, 12]. The association between severe neuronal loss in the LC and AD is strongest in the rostral and medial-dorsal projecting neurons [13–17], which has a major impact on disease outcome given that the loss of LC neurons reduces the availability of NA in the forebrain, hippocampus, and other target-regions; degree of LC cell loss has been shown to be highly correlated with global cognitive score, neuropathological accumulation, duration and severity of illness in elderly patients [16, 19]. Consequently, the disruption of the LC-NA pathway may very well be at the epicenter of the development of AD [1, 20] (Fig. 2).

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Fig. 1

Location of the locus coeruleus. The LC (circled) is located on the lateral floor of the fourth ventricle and upper dorsolateral pons.

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Fig. 2

Physiological and pathophysiological implications of the LC-NA system. The LC-NA system is involved in a host of physiological functions (shown via blue line). However, as the LC starts to falter, these mechanisms begin to weaken resulting in various AD symptomology (shown via dashed line). In reverse, mental stimulation of the LC, provided by anything novel and salient, leads to improved cognitive reserve (shown via green line).

Evolution of sex as a risk factor for AD

Studies examining patients have highlighted the disproportionate AD vulnerability of females over males, a ratio of approximately two to one [21], has brought forth valuable discoveries of sex differences in areas such as onset and conversion [22], rate of cognitive decline [23, 24], and brain atrophy [25]. Significant findings from these studies emphasizes the substantial consequence that disregarding sex may have for the vast range of current studies that do not sufficiently consider sex as a moderating variable in experimental, clinical, and therapeutic studies, and in identifying potential gender-specific prevention and treatment approaches to AD. Ongoing research to explain higher female incidence AD rate is primarily interested in risk factor profiles and prevention of AD, specifically heeding the effects of the apolipoprotein ɛ4 allele (APOE ɛ4) variant and the diminution of ovarian hormones; however, current studies have yet to determine or justify why the ratio exists.

For consideration of estrogens research

Female and male sex hormones include progesterones, androgens, and estrogens; however, the levels in which these hormones are produced differ depending on their sex, whereby androgens are more relevant for males, estrogens are more critical for females. Although all aforementioned sex hormones have their role to play, estrogens are of primary concern regarding females, considerably more so when females begin approaching the age range of perimenopause, menopause, and postmenopause. In females’ reproductive years, estrogens are predominantly produced by the ovaries and adrenal glands. Although estrogens are primarily known for their capabilities regarding female reproduction, these estrogens also circulate through the BBB in order to reach the brain and become a “master regulator” of biological functions as well as aid in neuroprotective effects [27]. The classification of estrogens contains three forms of the sex hormone: estrone (E1), estradiol (17β-estradiol or E2), and estriol (E3). Of these three estrogens, 17β-estradiol is the most prominent and highly researched form of estrogens. In addition to circulating estrogens produced by the females’ reproductive organs, 17β-estradiol can also be produced endogenously in the brain, also known as brain-derived estrogen [27].

In the latter part of a female’s lifetime, females will undergo stages of perimenopause, also known as menopausal transition, menopause, and postmenopause, respectively. Perimenopause typically begins at an average age of 47 and persist for approximately 5–8 years [28] and is denoted by females experiencing irregularity of duration and time between menstrual cycles, reproductive senescence, as well as, a gradual decline in ovarian hormones [29, 30]. Menopause typically occurs among females who fall in the age range of 48 to 52 years of age on average [31], and is defined as the 12-month period of amenorrhea where estrogens (evaluated by 17β-estradiol levels per STRAW+10) begin to rapidly decline [29]. After 12 months of cessation of menses, the occurrence of the final menstrual period can be confirmed, as well as the beginning of postmenopause, a stage in which females cease to menstruate and estrogens (evaluated by 17β-estradiol levels per STRAW+10) continue to decline for approximately 1 year, after which the estrogens begin to stabilize at the lowest levels in a female’s lifespan [29, 30]; it is also of note both brain-derived and circulating 17β-estradiol mirror the same amount of significant decline when postmenopausal females were compared to females who were premenopausal [32].

As previously mentioned, the classification of estrogens contains E1, 17β-estradiol or E2, and E3; however, it has been brought to our attention that the field of neuroscience commonly uses the umbrella term “estrogen” as an all-inclusive term for estrogens. As a consequence of the utilization of this umbrella term, the type of estrogen being referred to in numerous studies consulted for this prospective paper was ambiguous and resulted in our assumption that studies were most likely discussing 17β-estradiol when using “estrogen.” Therefore, it must be mentioned that although we suspect this report is highly representing the effects of 17β-estradiol, the potential contributions and effects of other hormones, such as, E1, E3, and progesterone, should not be neglected and must be considered when pondering females and AD. Furthermore, this limitation accentuates an area of research that neuroscience must improve upon. Moving forward, it is critical for researchers to 1) be more specific and provide more thorough descriptions when discussing sex hormones including estrogens, as well as 2) conveying whether they are referring to circulating or brain-derived estrogens in order to prevent obscurity of information, and 3) identify if females fall within reproduction, perimenopause, menopause, or postmenopause by using an outlined set of criterion, such as the STRAW+10 criteria [29]. This issue should be addressed promptly considering the upward trend in research regarding sex differences in AD. Finally, it must be noted that the specific form of estrogen will be documented in this review if it was identified; however, due to the forgone impediment, the majority of the evidence provided will use the term “estrogens.”

Estrogens influence on LC-NA regulation

By way of various regulatory mechanisms, gonadal hormones, such as estrogens, have significant effects on human brain function, including cognition, bioenergetic systems, and homeostasis [27, 33–35]. Estrogens’ direct ability to modulate LC activity is promoted by the presence of both nuclear estrogen receptors (ER) ER-α and ER-β and cell-membrane ER subtype G protein coupled estrogen receptor 1 (GPR30) found in wide distribution throughout the LC [36]. Additionally, studies looking at various male and female rat species have depicted that estrogens plays a significant role in facilitating sex differences in LC-NA morphology, from embryonic development into adolescence [37, 38] (for more details, see section Selective vulnerability and multiple clinical phenotype). Likewise, studies using ovariectomized female rats have exhibited that estrogens have a considerable impact on LC function by acting as a presynaptic modulator of NA release by altering the level of enzymes synthesizing NA, such as tyrosine hydroxylase and dopamine β-hydroxylase [39, 40]. In addition, estrogens are a key regulator in the degradation of NA by reducing catechol-O-methyltransferase levels, an essential enzyme needed for the breakdown of NA [41]. Given the evidence regarding estrogens’ effect on humans, and if the findings from the aforementioned rat studies are translatable to humans, this suggests the females could have an increased capacity for NA production and release.

Considering estrogen’s strong influence on LC-NA regulation [42, 43], and menopause causing a rapid loss of the ovarian sex-hormones in all females’ midlife, we hypothesize the loss of estrogens may explain the decline of the female LC-NA system, resulting in an increased risk of developing AD. This perspective piece highlights three key determinants of AD in which estrogens and the LC-NA make significant contributions that require further examination: namely neuroinflammation, BBB, and APOE ɛ4.

Future experiments and validation studies

Hormone replacement therapy (HRT) studies are of great popularity given the link between estrogens depletion and the increased risk of AD; although previous trials are not without debate and limitations [118], their contributions regarding HRT and female AD are invaluable assets that have facilitated ideas for future research. The past two decades have provided us with evidence that has not strongly supported the hormonal loss hypothesis in relation to cognitive function and/or dementia risk [119]. These studies have done well to incorporate various sex hormones in multiple combinations through multiple application methods. The Women’s Health Initiative (WHI) conducted a study on postmenopausal females 65 years and older [120]. Upon examination of the effects of estrogens alone (conjugated equine estrogens (CEE)), estrogens plus progestin (CEE plus medroxyprogesterone (MPA)), Premarin, a CEE that contains estrone and 17²-estradiol, as well as MPA, the WHI concluded that not only are the use of these HRTs not recommended but that the risks (of cancer, cardiovascular, and dementia) outweighed the benefits [121, 122]. A similar study, the Cache County Study (CCS), included postmenopausal females of 65 years of age or older (oophorectomized and non-oophorectomized) who reported uses of either “unopposed” or “opposed” estrogens [123]. The results of CCS indicated that postmenopausal females who began HRT 1–5 years from menopause exhibited a trend toward AD risk reduction, whereas participants who began HRT closer to or after menopause showed no association to lower AD risk [123]. A third study, The Kronos Early Estrogen Prevention Study (KEEPS), examining postmenopausal, healthy, non-hysterectomized females found no cognitive benefits after participants initiated HRT for four years via oral CEE plus micronized progesterone or transdermal estradiol plus micronized progesterone [124]. Additionally, The Early Versus Late Intervention Trial with Estradiol (ELITE) study looked to identify if utilizing oral micronized 17β-estradiol with progesterone gel for five years would have any effect on cognitive abilities in females who were more than 10 years postmenopausal [125]. ELITE concluded with no affects being evident in verbal memory, executive functions, or global cognition [125]. Taken together, the major critique of the previous four studies includes participants being in the postmenopausal stage, thus prompting the notion that future experiments must consider hypotheses such as estrogen administered into a healthy environment, “healthy cell bias” [119], and the efficacy of HRT in relation to the timing and onset of menopause, “window of opportunity”[126]. There has been some evidence supporting the timing hypothesis of HRT in observational studies where females have self-reported menopause status, timing of HRT initiation, and if opposed or unopposed estrogen was utilized [126]. Together, these observational studies provide support for the timing hypothesis given that each study’s results showed reduced risks of AD in groups that began HRT in earlier stages of their life [123, 128]. These findings stand in stark contrast compared to the previous four studies mentioned, particularly a follow-up study to the CCS which identified females who began HRT 1–5 years before menopause had a 30% reduced risk of AD, and a 37% reduced risk when taking HRT for 10 or more years [123].

In order to validate the present hypothesis, it is essential for future studies to persist in identifying sex differences in the LC-NA system. Moreover, it is imperative that studies are translated from rodents to humans so that we may discontinue drawing inferences from these studies and confirm the effects in humans. Additionally, our investigation of previous publications determined that a majority of animal research and experimental treatment trials are largely dominated by work carried out in males. In order for scientific research to excel, experimental and clinical design must undergo considerable modifications such as routinely stratifying data by sex and ensuring studies are statistically powered to detect interaction effects between sexes. Furthermore, a set list of guidelines must be established for reporting sex differences [129], otherwise inconsistencies and uncertainties will remain in our understanding of female AD.

Future experiments may embrace the goal of working towards establishing an interrelated timeline connecting the dysregulation of the LC-NA system, the decline of sex hormones, and AD vulnerability together. This will allow for studies conducted to utilize a more relatable timeline that associates the females’ stages of menopause with the advancement of neuropathology in the LC using the pre-established BB stages. The institution of this timeline will enhance the investigation of the hormonal loss hypothesis when testing how HRT affects the LC-NA system and enable studies to place consistent, corresponding timeframes for their findings regarding “window of opportunity” and “healthy cell bias.” Taken together, these future investigations are instrumental in exploring methods to upregulate estrogens and LC-NA mechanisms in order to deter further neuropathological accumulation and neurodegeneration. It is vital to address this hypothesis promptly seeing that the increase in today’s lifespan could indicate that on average females would spend up to one-third of their life without production of estrogens [130].

Aging

The increased longevity of females is one of the most argued justification for the increased risk of AD and has recently come under more scrutiny as of late [131]. Evidence indicates aging alone is not a suitable determinant for LC degeneracy [132]; however, our present theory insinuates that aging is notable given the association of age and onset of menopause in the majority of females. As mentioned previously, the current mean age of the onset of menopause is approximately 51 years of age, with a mean range of 48 to 52, and perimenopause typically begins at an average age of 47. This is significant due to these age ranges of the emergence of perimenopause and menopause, respectively, coinciding with BB stages Ia, Ib, I, and II. At these ages, a vast majority of human autopsy brains were classified in BB stages Ia and Ib whereby prominent AT8 immunoreactive pretangle material was displayed, noted as the source of argyrophilic neurofibrillary lesions, thus facilitating neuronal vulnerability [3]. Additionally, approximately half were classified as BB stages I and II at which point Gallyas-positive neurofibrillary lesions were manifesting in the entorhinal regions, indicative of the potential initiation of neuronal deterioration that could occur in future BB stages [3]. A highly significant correlation between AD-related pathologic findings and age has been found in females, yet no current significant difference has been seen between females and males in early and mid BB stages. However, more significant variations are seen between males and females as individuals increase in age. Given the strong influence estrogens have on LC-NA regulation [42, 43], and the fact that females suffer from greater implications than males the further away they get from perimenopause and menopause age, it must be considered if a decrease in estrogens may have a disproportionately negative effect on the LC-NA system of females, thus resulting in an increased risk of developing AD.

Selective vulnerability and multiple clinical phenotypes

Animal studies have depicted sexual dimorphism in LC morphology [37, 41], with sex differences in LC size, make up, and neuronal number, depending on the strain of rat used. Furthermore, studies using Wistar rats show developing females to have a higher volume and neuronal count [38, 133], and this, together with sex differences in dendritic structure [37], may be due to the influence of estrogens during LC neurogenesis [38, 134]; female dendritic trees have been shown to be longer and more complex, with greater numbers of branch points and higher-order branching [37]. If these findings could be reproduced in human studies, this may support the prospect that females receive higher levels of synaptic input and process additional information coming into the peri-LC, from regions such as the periaqueductal gray and nucleus tractus solitarius (NTS) [135]. The NTS can influence NA activity both directly via synapses on neurons in the LC, and indirectly via connections linking the LC to the amygdala and hippocampus [136]. Alternatively, the NTS is also involved in the regulation of gastrointestinal activity along with the vagus nerve, which, as mentioned previously, could result in exposing the LC to toxic agents [7].

Due to the LC mediating arousal and autonomic function, the potential multifaceted dendritic structure of the female LC and the increase in NA induced by estrogens allows for the potential of heightened emotional arousal response [37]. A repercussion of the increased stimulation seen in the female LC could be the rationale for hyperarousal resulting in and contributing to the increased rates of disorders seen in females [41], such as post-traumatic stress disorder, depression, and sleep disturbance, all of which share clinical phenotypes with, and are comorbid risk factors of AD and coincidentally are more predominant in females [137]. This connection between their modified LC-NA network and the presentations of behavioral manifestations in females emphasizes the need for further examination into the causes-and-effects of selective vulnerability in female AD.

An additional consideration regarding LC vulnerability stems from results of a recent mice study investigating the effects of 3, 4-dihydroxyphenylglycollaldehyde (DOPEGAL) on the LC indicated that monoamine oxidase A (MOA-A) metabolizes NA into DOPEGAL through oxidative stress, which in turn increased asparagine endopeptidase, and resulted in tau N368 cleavage which is susceptible to hyperphosphorylation, aggregation, and propagation, leading to noradrenergic cell death [138]. This study contributes significant information when considering our hypothesis given that estrogens and progesterones are both regulators of oxidative stress [139]. As mentioned previously, females begin to experience perimenopause and menopause, respectively; approximately when BB stages Ia and Ib, I, and II occur in humans, coinciding with the timing when pretangle and tangle material is observed, and neuronal vulnerability is facilitated. This is significant on account of the process of NA oxidizing to DOPEGAL and ultimately resulting in tau cleavage and noradrenergic cell death is conceivably protracted, and thus are not observable until later BB stages, leading us to speculate if the loss of estrogens and progesterones in early BB stages due to perimenopause and menopause is potentially one of the explanations of NA metabolizing to DOPEGAL due to the lack of the female’s ability to regulate oxidative stress.

Furthermore, findings from a recent study indicated similar results where increased levels of NA-metabolism were connected to greater cerebrospinal fluid phosphorylated tau in both female and male memory clinic patients [140]. Additionally, these findings were affiliated with a decrease in learning ability that was tracked over a 6-year timeframe; this observation is in line with the idea that changes in the LC prior to the accumulation of neuropathology takes time to intensify to a measurable degree which allows us to discern behavioral differences [140]. Collectively, these studies indicate oxidative stress, which is regulated by estrogens and progesterones, metabolizing NA ultimately results in neuropathology. Upon consideration of these results and taking our hypothesis into account, it is of substantial importance to advance this research by investigating the effects of sex differences, such as females undergoing the menopausal transition, may have on NA oxidization and if this results in increased neuropathology load and neuronal death in the LC.

Modifying risk factors

Potential preventative measures that have vastly emerged in AD literature are those of brain reserve and cognitive reserve [141]. Brain reserve pertains to the individual’s anatomical brain structure, and suggests a more complex morphological framework that includes increased synaptic and neurotransmitter receptor densities that would potentially be able to withstand consequences of neuronal loss or tolerate more detriment. Alternatively, cognitive reserve spotlights individuals’ functional resilience and suggests increased cognitive processes or more intricate neural networks that aid in creating a higher degree of build-in redundancy [142]. Currently and collectively, both brain reserve and cognitive reserve highly favor males as opposed to females. For instance, brain reserve strongly suspects that males increased cerebral brain volume is superiorly capable of withstanding the accumulation of pathology to that of females [143, 144]. This is further supported by evidence indicating females had significantly greater odds of AD given the identical amount of pathology to males [145], as well as female brain volumes declining faster in patients with mild cognitive impairment and AD [146]. However, bearing in mind the previously discussed preeminence of the female rodent LC morphology and if this is translatable to female human LC morphology, what it means for female brain reserve remains to be answered.

Conversely, a link between the characteristics of cognitive reserve, such as education, occupational attainment, and lifetime experiences, and the upregulation of the LC-NA system in both animal models and in vivo human studies has been alluded to [147]. An upregulated LC-NA system allows for an increase in the number of receptors on the target cell, permitting more effective signal transmissions needed for peak cognitive performance, while simultaneously releasing a protective mechanism against threats of inflammation and neuropathology [12, 149]. While the mechanism of cognitive reserve is still difficult to define, the model suggesting NA being the fundamental pillar that underpins a delay in AD pathology is something to consider. It is widely acknowledged that males/men surpass females/women in cognitive reserve on the basis of both sex and gender differences due to previous societal practices which resulted in less opportunity for cognitive enrichment for females/women. Moreover, a study comparing LC signal intensity and the established proxies of reserve (i.e., education level and occupational attainment) in a cognitively healthy population, showed older-adult females, on average, have  20% less LC signal intensity than older-adult males [150]. Conversely, a more recent study observed no sex-differences in age-related LC intensity associations [151]. These conflicting results may be due to different sample sizes and/or varying parameters of magnetic resonance imaging, thus continuation of improving upon the methodological approach is required to validate such findings. Nonetheless, a potential sex difference in LC signal intensity raises the question of what this means in regards to an indisposed LC in menopausal females (i.e., during a marked time of the depletion of estrogens). Does this affect females/women’s day-to-day cognitive capabilities or their ability to undertake cognitive reserve, and therefore losing out on the potential to compensate or modify the AD state? If so, we must discover how we may begin to exploit females’ ability to perpetuate cognitive reserve, thereby upregulating the LC-NA system, earlier on in life, in order to mitigate the foreseeable AD pathology that comes as a result of the decline of estrogens and LC-NA dysregulation.

Pathogenic predisposition and sequence of progression

Structural and metabolic characteristics of female APOE ɛ4 gene carriers contribute to a predisposition to pathophysiological dysfunction, resulting in neuropathological components of AD. The composition of phenotypic, LC morphological framework induced by estrogens, and demographic attributes establish the substructure that influences LC dysfunction and neuronal loss that accelerates AD pathogenesis. In the course of female AD, it is more likely that the combined neuroprotective functions of NA, the inflammatory response system, and the regulation of the BBB, with the additional support of estrogens, are able to hold off the disease until a critical threshold. We speculate a drastic decrease in estrogens and NA production results in the pathologic process of tau pathology and Aβ so severe that it can be observed in BB stage V and VI through LC cell loss and impaired cognitive function. Moreover, an overall loss of tropic support occurs, thus leaving the female brain incapable of producing an anti-inflammatory response and governing BBB integrity, in turn conducing a toxic neuronal environment. Neuropathologies intensifying, BBB dysfunctioning, and neuroinflammation rising creates a continuous fed forward cycle that contributes to the progression of the disease, and causes clinical signs of AD such as a reduction of neuronal plasticity and neurodegeneration to become more apparent, and are currently unable to be halted or reversed (Fig. 3).

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Fig. 3

Hypothesized route of female ad heterogeneity. We propose that sex and age, as it relates to the onset of menopause, increases female vulnerability due to the rapid loss of estrogens and its effects on the LC-NA system, thus accelerating the load of neuropathology that give rise to neurodegeneration and reduced synaptic plasticity. This hypothesized route not only plays a critical role in AD development, but also disproportionately effects females. Redrawn from Mravec et al. 2014 [1].

Mixed pathology

The exploration into sex difference and their frequency patterns of mixed neuropathologies have only recently begun [137]. However, according to a recent study involving autopsy-based investigations on human brains, females significantly exhibited signs of mixed AD and cerebrovascular pathology compared to males [152]. This finding raises intriguing questions regarding the nature and extent of the role in which the two critical components of our present hypothesis have given our previous explanation of the vitality of the BBB being heavily dependent on favorable LC-NA signaling the production of estrogens. It is therefore likely that a further connection may exist between the downfall of both the female LC and estrogens and an increase in the comorbidity of mixed pathologies, thus warranting future studies.

Biomarkers

Currently, the amyloid/tau/neurodegeneration (ATN) classification framework has seen a significant rise in hopes that it will assist in the diagnostic procedure, development of preventative measures, and treatment strategies for AD. ATN classification for AD focuses on the presence of Aβ pathology, tau pathology, and neurodegeneration. Prior research utilizing the ATN biomarkers, as well as, most LC investigations have yet to report any significant difference among males and females; however, sex differences have not been the predominant variable of consideration. In line with ongoing research, we support moving in the direction of focusing investigations on the LC as a new biomarker potentially capable of tracking prognosis and progression of AD, with a specific interest in sex differences. It is essential that further efforts utilize various methodologies, such as unbiased stereological analysis to assess LC cell population, volume, and neuronal death [132]. Additionally, capitalizing on enhancements new technologies provide to current techniques such as in vivo imaging [153] and positron emission tomography imaging [154] will be a critical component in measuring LC integrity and functionality, allowing us to overcome previous obstacles such as its small size and location. Combining these various methodologies will further facilitate our ability to validate the LC as an early-stage biomarker for AD, and incite further exploration into sex differences.

Translation potential (diagnostic implications)

Future research in pursuance of advancing early disease detection and improving upon investigational therapeutic approaches are of utmost priority. Neuropsychological testing upon exhibitions of cognitive deficits is one the primary courses of action to assess if AD has begun to manifest. However, the current assessment strategies not adjusting for sex differences indicates a significant shortcoming in the clinical diagnosis of AD, and may contribute to a myriad of misdiagnoses or late diagnoses in females.

Cognitive abilities have recently been recognized in both animal and human studies as being molded by gonadal steroids and the differences by which LC-NA mechanisms modulate the amygdala and hippocampus regions, and throughout the brain [155]. These factors contribute to males and females having unique patterns of activation and performance on emotional autobiographical and episodic memory, spatial ability, and perceptual processing tasks [155]. It has been proposed that the mechanism of action by which the LC assists males and females differently is in how they distinguish and redirect attention to salient stimuli and how they encode and retrieve specific information. Such discrepancies become behaviorally apparent as males outperform females on recall tasks for central information, spatial rotation, and navigation tasks, while females excel on recall tasks for ancillary information, objection location, and verbal memory tasks [130, 155].

Acknowledging the role the LC and estrogens play in the sex-specific strengths and disadvantages consistently present in cognitive processes may have direct bearing on neuropsychological testing, so much so that it ought to be accommodated for in the formation of sex-adjusted normative data and sex-based cut-off scores used to differentiate normal aging and preclinical AD. Accordingly, this will increase the likelihood of preventing AD symptoms being masked during examination and further improve validity of AD diagnosis. Sex-specific neuropsychological assessments will have vast implications for the monitoring of AD progression, as well as, measuring the effectiveness of experimental treatments.