Influence of age and sex on presymptomatic phases of neurodegenerative diseases: Focus on multiple sclerosis and Alzheimer’s disease

Abstract

Neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer’s dementia (AD) demonstrate an ever-evolving disease continuum. The presymptomatic phase of neurodegenerative diseases provides a window of opportunity to detect disease-specific changes and abnormalities early on and potentially intervene right away, before clinical symptoms occur. Age and sex are key modifiers of the presymptomatic phase of neurodegenerative diseases. In presymptomatic MS, younger age and male sex are main risk factors for transition to symptomatic MS, whereas older age and male sex are important predictors of the direct transition to primary progressive MS. In cognitively unimpaired adults, age is the strongest risk factor for AD and the lifetime AD risk after >65 years is higher in women versus men. The prevalence and future disease severity of AD is further modified by factors such as apolipoprotein Eε4, ovarian hormones, and menopause in women. Biomarkers are instrumental in detecting and monitoring abnormalities and underlying disease mechanisms in vivo, that are already present in the presymptomatic phase. Evaluating the influence of age and sex on presymptomatic phase of neurodegenerative diseases, particularly through biomarkers, contributes to the enhanced patient selection for clinical trials, optimization and individualization of patient management and development of new therapeutics.

1. Introduction

In neurodegenerative diseases with a long-term biological disease continuum such as in multiple sclerosis (MS) and Alzheimer’s dementia (AD), individuals already have ongoing disease-specific pathological changes, before clinical symptoms become evident. This key period corresponds to the presymptomatic phase in the course of neurodegenerative diseases.

Although individuals do not have any clinical symptoms during the presymptomatic phase, this disease phase can reliably be evaluated and monitored in vivo by numerous biomarkers. With the use of biomarkers, the identification of neurodegenerative diseases in their presymptomatic phase is the ultimate goal in disease management. It results in early detection and evaluation of often subtle preclinical changes and abnormalities that are underway, forecasting future clinical onset and deterioration, serving as a canary in the coal mine. The evaluation of the presymptomatic phase may also enable better understanding of disease mechanisms, development of new treatment strategies and early intervention to modify the disease course and clinical outcomes. Exploring the influence of age and sex on presymptomatic phases of neurodegenerative diseases may further contribute to better disease management by strategically optimizing and individualizing patient care.

2. Multiple sclerosis (MS)

2.1. Influence of age and sex on presymptomatic MS

Multiple sclerosis is the most common demyelinating disease of the central nervous system (CNS), and women are more frequently affected by MS than men. The current female-to-male ratio is increasing and ranges between 2:1 and 3:1 with a potential contribution of increase in female response to epigenetic and environmental changes.(1–4) In addition to sex differences in MS risk; disease activity, progression, and disability accumulation also differ between female and male patients.(5) Similar to sex, age plays a crucial role in MS disease course, impacting many aspects of the disease, including relapse frequency, relapse recovery, progression and disability accumulation.(6)

The presymptomatic phase of MS, otherwise known as radiologically isolated syndrome (RIS), is the earliest detectable phase of MS in adults and children.(7, 8) Individuals with RIS have no clinical symptoms attributable to a CNS demyelinating disease, but their brain and/or spinal cord magnetic resonance imaging (MRI) demonstrates lesions characteristic of demyelination based on the RIS diagnostic criteria.(7, 9, 10) Most of these individuals also fulfill the newly proposed updated MS diagnostic criteria, which further supports that the MS disease course is a biological continuum rather than a symptom-reliant concept.(11)

Similar to symptomatic MS, the presymptomatic phase of MS is more common in women compared to men.(12, 13) Individuals with presymptomatic MS can develop symptomatic MS, including relapsing MS and progressive MS. Of the presymptomatic MS individuals, about one-third in five years(14) and about half in 10 years(12) transition to symptomatic MS. Therefore, once the RIS and presymptomatic MS diagnoses are confirmed, risk factors for transitioning to symptomatic MS should be evaluated. In RIS, in addition to spinal cord, infratentorial or gadolinium-enhancing lesions on MRI, cerebrospinal fluid (CSF) abnormalities and increase in neurofilament-light chain, younger age (<37 years), and being male are among the main risk factors for developing clinical symptoms and transitioning to symptomatic MS.(14, 15) Remarkably, individuals with presymptomatic MS can also directly develop progressive MS, which is classified as primary progressive MS.(16) Older age is the main determinant of transition to progressive MS, regardless of the preceding MS phenotype.(17–19) Therefore, it is not surprising that older age is an important risk factor for transitioning to primary progressive MS in individuals with RIS.(16) In addition to older age and having spinal cord lesions; male sex is also identified as a strong risk factor for transitioning from RIS to primary progressive MS (Fig. 1).(16) Moreover, it was reported that Kappa free light chain index (KFLC index) can predict new disease activity in both RIS and clinically isolated syndrome, however, the KFLC index was not impacted by sex while it decreased with age.(20)

Figure 1.

Risk factors of transitioning from presymptomatic MS to progressive MS. Subsequent to the incidental detection of multiple lesions on brain MRI (A) and a lesion on spinal cord MRI (B), this male patient without any neurological symptoms was diagnosed with RIS in the 6^th decade. During follow-up, a new spinal cord lesion developed (C), and he eventually transitioned to primary progressive MS in the 7^th decade. In addition to having spinal cord lesions, older age and male sex are among the main risk factors for transitioning from presymptomatic MS to primary progressive MS.

Reproductive milestones such as pregnancy seem to play a role in RIS-to-symptomatic MS evolution as well. In a group of women with RIS who were followed for up to seven years, the transition time to symptomatic MS was shorter in women who had pregnancy compared to women without pregnancy.(21) In addition to higher rates of clinical events, the pregnant group had higher rates of new radiological activity than the nonpregnant control group.(21)

2.2. Age and sex differences in pediatric RIS

Establishing the lifetime course of the MS disease continuum, on one end of the age spectrum, children can have RIS and children with RIS have an even higher risk (42% risk within two years of the index MRI) of developing symptomatic MS.(22) In a cohort of pediatric RIS, age and sex did not differ between children with and without a first clinical or radiological event.(8) However, interestingly, age and sex differences were detected in the diagnostic workup of individuals with pediatric RIS. In a multicenter study, younger versus older children (≥12 years) and male versus female children less commonly underwent CSF analysis for diagnostic workup, indicating the necessity to develop comprehensive diagnostic guidelines for children with RIS as well.(23)

2.3. Sex and hormonal differences at the time of symptomatic MS onset

The existence of age and sex differences in individuals at the time of symptomatic disease onset highlights the ongoing influence of age and sex in the MS disease course, from presymptomatic MS to progressive MS. In an MS imaging study on premenopausal women, postmenopausal women and men, normalized total brain volume, normalized cortical volume, and normalized brainstem volume were smaller in age-matched men compared to premenopausal women, whereas the brain volumes were similar between age-matched men and postmenopausal women at the time of symptomatic MS onset (MRI obtained within around 45 days of clinical disease onset).(24) Deficiency in sex hormones, particularly the lack of estrogen associated with menopause seem to modify MS course through neurodegenerative changes and progression not only during the symptomatic phase of MS(25) but also before clinical symptoms become evident, detected by brain atrophy on MRI.(24)

2.4. Age and sex differences in symptomatic MS

In contrast to the limited data in the presymptomatic phase of MS, age and sex differences in symptomatic MS are relatively well established. MS disease onset is usually earlier in women than in men(26) and women tend to have more inflammatory activity early in the disease course,(27) particularly until the age of menopause. Female sex was reported as an independent risk factor of developing relapses within the first five years of MS diagnosis(28) whereas it was a protective factor for transition to progressive MS.(28) However, in men, neurodegeneration is more prominent and the onset of progressive MS is earlier compared to women.(29, 30) Although the relapse frequency is less common in men,(27) the recovery potential from relapses is also lower compared to women.(3) Consequently, this sex dichotomy in relapse recovery contributes to faster disability accumulation early in the disease course(31) and earlier transition to progressive MS in men.(32) Despite better relapse recovery potential in women in early MS, the sex difference in inflammatory disease activity likely diminishes after the age of 50, which also often overlaps with menopausal transition.(33) Moreover, once women transition to progressive MS, they tend to experience a rise in the rate of disability accumulation and reach comparable levels of disability severity to men.(34)

In addition to sex differences in clinical characteristics, there are sex differences in imaging and laboratory biomarkers of MS.(35) Women have a higher likelihood of having T2 hyperintense and enhancing lesions, whereas T1 hypointense, infratentorial and spinal cord lesions as well as brain and spinal cord atrophy tend to be higher in men.(36–40) Furthermore, in patients with MS, female sex and younger age are associated with higher KFLC index, which is an important MS diagnostic tool.(41)

Age is another key factor in MS, impacting the entire MS disease continuum including disease onset, disease activity, treatment response, disability accumulation and progression.(6) Older age at disease onset is often associated with poorer prognosis.(42) Relapse frequency declines with older age, however, relapse recovery potential declines with older age as well.(43) Because the inflammatory disease activity tends to attenuate with age, it is not surprising that there is a decrease in the efficacy of DMTs(44) and an increase in adverse effects with age.(45) Furthermore, older age is the main determinant of evolution to progressive MS(19) and associated with neurodegeneration and CNS atrophy.

2.4. Influence of age and sex on treatment response in RIS clinical trials

The presymptomatic phase of MS serves as a critical window of opportunity for the earliest possible intervention to delay or halt the evolution of symptomatic MS, especially in individuals who have higher number of risk factors to transition to symptomatic MS.(15) Early initiation of disease modifying therapies (DMTs) in symptomatic MS is recommended because it significantly contributes to stable disease with no inflammatory activity and lower disability.(46, 47) The knowledge gap in DMT use and efficacy in RIS has been addressed by two randomized, multicenter, double-blind, placebo-controlled clinical trials conducted in RIS. These clinical trials “Assessment of Tecfidera in Radiologically Isolated Syndrome” (ARISE)(48) and “Teriflunomide in Radiologically Isolated Syndrome (TERIS)”(49) showed efficacy in preventing or delaying the first clinical event in individuals with RIS. In both ARISE and TERIS trials, the time to a first clinical event remained significant after adjusting for age at diagnosis and sex. However, the immunomodulatory response may differ between two sexes in MS, especially considering differences in immune function and hormones between women and men. Even though age and sex were not part of pre-specified stratification in these trials, future evaluation, possibly with post hoc stratification, may enlighten the influence of age and sex on the treatment response of the presymptomatic phase of MS. This will help optimize treatment strategies in individuals with presymptomatic MS by an expert MS team.(15)

Similarly, in symptomatic MS, most of the DMT trials lacked pre-specified sex-specific analysis on efficacy or adverse effects and the potential influence of reproductive milestones such as menopause has not been considered.(50) Despite the scarce data suggesting a difference in treatment response between male versus female patients, particularly in patients on interferon-beta,(51, 52) there is still no consensus on sex differences in treatment response in MS. However, there seems to be sex differences in DMT preference and discontinuation. In a recent MS registry study, the rate of DMT escalation due to relapse activity was lower in women compared to men.(53) Moreover, women were more likely to discontinue moderate- or high-efficacy DMTs and the most common reason for DMT discontinuation was family planning.(53)

All in all, more studies are needed on age and sex differences in presymptomatic MS, especially in biomarkers of presymptomatic MS, including advanced MRI and molecular positron emission tomography (PET).(54, 55) Biomarkers are essential for presymptomatic MS diagnosis and are key tools to better evaluate the role of age and sex in the presymptomatic phase of MS. This can eventually help better identify tailored risk factors of transitioning to symptomatic MS, predict future disease outcomes including disability accumulation and more effectively measure the treatment response during the presymptomatic phase of MS.

3. Alzheimer’s disease (AD)

3.1. Influence of age and sex on presymptomatic phase of AD

Alzheimer’s disease (AD) is the most common type of dementia and older age is the strongest known risk factor for developing AD, especially after the age of 65, both in women and men.(56) One in ten adults who are ≥65 years of age has AD and the prevalence continues to rise significantly beyond the seventh decade.(57)

There are sex differences in AD risk, presentation, progression and treatment response.(58–60) The lifetime risk of AD after the age of 65 is higher in women than in men and the prevalence of AD is twice as high in women than in men.(61–63) Moreover, women have an increased risk of having more severe AD pathology,(64, 65) and a greater AD-related cognitive decline.(65, 66)

Female sex is a possible strong inherent risk factor for AD(67) and inflammatory responses tend to be higher in women, more severely impacting the immune system.(68) Furthermore, men in midlife have a higher mortality rate due to cardiovascular disease. On the other hand, women have a higher life expectancy, predisposing them to cardiovascular disease risk and other comorbidities including dementia for a longer duration, compared to the selective survival of men with good cardiovascular health and consequent decrease in dementia risk in these men.(69–71)

Independent of enhanced longevity in women, the elevated lifetime risk of dementia in women compared to men may also be modulated by other specific risk factors(60) such as apolipoprotein E ε4 (APOEε4) genotype(72) and changes in ovarian hormones, mainly associated with menopause.(73) APOEε4 is the strongest risk factor for developing sporadic AD(74) and women with APOEε4 genotype have a greater risk of developing AD, particularly at younger ages.(75) The cognitive deterioration is faster in women compared to men,(76) which is further enhanced in the presence of the APOEε4 variant and high amyloid-β deposition.(77) The higher incidence of behavioral symptoms such as agitation in women may also contribute to the sex differences in the rate of cognitive decline.(58)

3.2. Age and sex differences in biomarkers in presymptomatic phase of AD

There are significant age-associated changes leading to deterioration in brain health and cognitive performance in cognitively unimpaired individuals.(78) Subtle changes and abnormalities likely precede the gradual decline in cognitive domains. For early diagnosis and staging of AD pathology, biomarkers can serve as essential tools to effectively detect these presymptomatic changes in cognitively unimpaired individuals, decades before they develop cognitive impairment (Fig. 2).(79) They can also be used for identification of presymptomatic individuals for prevention trials in AD.(80)

Figure 2.

Use of biomarkers in the presymptomatic phase of neurodegenerative diseases

In neurodegenerative diseases with an ever-evolving disease continuum, the presymptomatic phase marks the period when individuals do not have any clinical symptoms but already have ongoing underlying disease-specific pathological changes and abnormalities. For example, in the presymptomatic phase of AD, biomarkers such as MRI, amyloid-β PET and tau PET, are essential tools to detect and monitor AD-related brain pathology decades before individuals develop clinical symptoms. Once the threshold for clinical symptoms is exceeded, individuals first enter the prodromal phase of mild cognitive impairment. As pathological involvement continues to spread throughout the brain and as cognitive function deteriorates, individuals enter the dementia phase of AD. During this downstream of events and transitions, the use of biomarkers provides the key opportunity to identify individuals in the presymptomatic phase and carefully follow their progression. Notably, determining the impact of age and sex on the presymptomatic phase, mainly through biomarkers, helps further understand disease mechanisms and better optimize and individualize management.

In cognitively unimpaired individuals, total and regional (including prefrontal and medial temporal lobes) brain volumes as well as white matter volume on MRI decrease with age.(81, 82) However, these macroscopic structural changes on MRI mainly reflect later brain abnormalities, whereas other advanced imaging techniques such as diffusion MRI can detect age-related and possible earlier microstructural changes in white matter integrity in cognitively unimpaired individuals.(83, 84) Both diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics strongly correlate with age in cognitively unimpaired adults with NODDI potentially having a better ability to capture early neurodegenerative changes as an effective brain health biomarker.(85) Among these metrics, DTI mean diffusivity and NODDI free water fraction were reported as very strong predictors of cognitive function.(86) Moreover, compared to structural MRI, NODDI was more sensitive to older age and early AD.(85) Particularly free water fraction on NODDI showed a better performance in distinguishing cognitively unimpaired adults from patients with mild cognitive impairment (MCI) and correlated better with regional tau deposition than structural metrics.(85)

Amyloid-β PET and neurofibrillary tangle tau pathology are the core biomarkers of AD, based on the revised AD diagnostic and staging criteria.(87) In a landmark study, imaging biomarkers were classified into eight groups (A−/+=amyloid negative/positive, T−/+=tau negative/positive, N−/+=neurodegeneration negative/positive) to better characterize the heterogeneity of pathological profiles in cognitively unimpaired individuals.(88) Age was the main determinant of the switches between the biomarker-based pathological profiles and until the late 70s, the most common pathological profile was the triple-negative group in both sexes in cognitively unimpaired individuals.(88) After the age of 50, the prevalence of the triple-negative group (A−T−N−) was decreased and the prevalence of triple-positive (A+T+N+) and A−T+N+ groups was increased.

Another study on cognitively unimpaired individuals showed that the hippocampal atrophy started around the age of 30 and gradually deteriorated with age, with a steeper decline after the age of 60.(89) It was worse in men than in women, primarily after 60 years of age.(89) In parallel, memory scores were worse in men compared to women. However, in the same study, interestingly, amyloid-β PET findings did not differ by sex,(89) particularly in cognitively unimpaired individuals older than 70 years when amyloid-β positivity on PET starts to become more common.(90) In contrast, CSF tau level as well as tau deposition on PET were higher in women compared to men. (91) In addition to faster rates of brain atrophy in women compared to men,(92) women in the AD trajectory showed higher tau deposition early on(93) and higher entorhinal tau deposition correlated with higher amyloid-β load in female cognitively unimpaired individuals.(91)

Although, in sporadic AD, APOEε4 allele is the strongest genetic risk factor for both sexes, in women, APOEε4 positivity leads to a higher risk of MCI/AD and a higher risk of MCI to AD transition.(72) In cognitively unimpaired individuals(94, 95) and patients with MCI,(72) CSF tau levels were higher in female APOEε4 carriers than male APOEε4 carriers, and the higher CSF tau levels in female APOEε4 carriers correlated with higher amyloid-β levels.(94) Furthermore, having one or two APOEε4 alleles had a more detrimental impact on hippocampal atrophy and cognitive impairment in women.(96)

In a meta-analysis on dominantly inherited AD, initially, while hippocampal atrophy was similar between two sexes, female mutation carriers demonstrated better performance in delayed recall and processing speed.(59) However, female carriers had more severe deterioration in MRI biomarkers of neurodegeneration as well as cognitive impairment as the disease progressed. Like in sporadic AD, amyloid-β deposition on PET was similar between two sexes.

In sporadic AD, interestingly, as discussed above, the amyloid-β loads in PET or CSF do not differ significantly between female and male patients.(65, 77, 89) However, sex still seems to be a modifier in AD-related cognitive decline because women with higher amyloid-β deposition showed faster cognitive decline than men.(77) Moreover, global AD pathology was higher in women compared to men but this difference was mainly driven by neurofibrillary tangles rather than the amyloid-β load.(65) The higher global AD pathology was also more likely to present as clinical dementia in women compared to men.(65) The level of cognitive impairment tend to be also more severe in women due to higher tau burden and brain atrophy compared to men.(97)

Because amyloid-β load does not appear to differ by sex,(72, 98) this may support an initial similar and equivalent amyloid-β pathology between two sexes but after the initiation of amyloid-β deposition, sex differences occur downstream with a higher likelihood of APOEε4 triggering an acceleration of tau-related pathology in women than in men.(67, 93, 94)

3.3. Influence of sex hormones on presymptomatic phase of AD

Sex hormones have varying organizational influences on the critical periods of neural development and neural changes.(99–101) Age-related depletion of sex hormones is associated with future cognitive decline in cognitively unimpaired individuals.(67, 102) Considering the neuroprotective effects of sex hormones, the difference in the rate of sex hormone depletion between women and men likely contributes to sex differences in AD risk, prevalence and severity.(103)

In parallel, in cognitively unimpaired older adults, menopause can exacerbate the elevated tau deposition on PET in women. In a study on men and pre- and postmenopausal women, postmenopausal women had higher amyloid-β and tau deposition than age-matched men in parietooccipital and middle frontal regions, whereas there was no difference between premenopausal women and age-matched men.(104)

Interestingly, the sex and menopause differences in parietooccipital and middle frontal regions on tau PET were not moderated by amyloid-β load or APOEε4 positivity, suggesting a menopause-associated exacerbation of tau vulnerability independent of AD-related pathways in cognitively unimpaired older women.(104) In another study, symptomatic menopausal and perimenopausal women showed greater amyloid-β deposition and brain atrophy compared to asymptomatic menopausal women and men.(105) Amyloid-β deposition was more significant in APOEε4 positive menopausal women than other groups, suggesting that menopause plays an important role in presymptomatic phase of AD and cognitive aging.

Differences in the rate of hormonal loss in women versus men, with women having a more rapid and dramatic decline whereas men having a more gradual and slow loss, further contribute to the sex differences in future cognitive decline in cognitively unimpaired individuals. The rate of sex hormone loss is even faster in women who undergo bilateral oophorectomy. Premenopausal bilateral oophorectomy (PBO) before 46 years of age is associated with an increase in dementia risk(106) as well as a faster accumulation of multimorbidity.(107) Compared to controls, in cognitively unimpaired women with PBO before 50 years of age, the parahippocampal-entorhinal cortex was thinner, and the entorhinal white matter fractional anisotropy was lower,(108) supporting that structural changes in medial temporal lobe may occur after abrupt hormonal changes due to PBO in cognitively unimpaired women. In a follow-up study,(109) compared to women who did not undergo PBO, women with early PBO (before 46 years of age) showed age-dependent increase in amyloid-β deposition, greater tau deposition at higher amyloid-β deposition, and AD-like pattern of neurodegeneration displayed by the reduction in entorhinal cortical thickness, the earliest cortical region to be affected by AD.(110) These findings further suggested considering avoiding surgical menopause in the absence of high genetic ovarian cancer risk and other malignant conditions. As another potentially modifiable risk factor, in recently postmenopausal women with low cardiovascular risk, maintaining normal blood pressure was found important to decrease the risk of white matter hyperintensities later in life and it was independent of short-term menopausal hormone therapy.(111)

There are conflicting results on the impact of menopausal hormone therapy on dementia risk in women and the lack of consensus is possibly driven by the variability across women.(112) Timing of menopause, type of menopause and the presence of vasomotor symptoms are the main determinants of this variability. Currently, the North American Menopause Society does not recommend the use of menopausal hormone therapy for prevention of cognitive impairment and dementia.(113) For the largest group of women with normal age at menopause (45–54 years), if they experience vasomotor symptoms, hormone therapy could be initiated. The recommendation on not to use hormone therapy for dementia risk should not be applied to women with premature/early menopause (<45 years). This specific group of women should rather use hormone therapy from menopause onset until the age of 50 to 52, by following the therapeutic window of opportunity of appropriate dose and time.(114)

3.4. Influence of age and sex on treatment response in presymptomatic phase of AD

In the presymptomatic phase of AD, even though the individuals are cognitively unimpaired, the neuronal loss detected by biomarkers already starts and continues downstream long before the clinical symptom threshold is exceeded. However, ideally, these individuals in the presymptomatic phase can benefit optimally from a therapeutic intervention. In contrast, beyond this point, with an intervention during the symptomatic phase, while a potential biological efficacy can be observed using biomarkers, it can still be too late to obtain clinical efficacy.(115) Therefore, in addition to the benefits of early intervention during the presymptomatic phase of AD, accounting for the differences in age and sex at this phase can better help modify disease course and prevent or delay clinical symptom onset with a more tailored disease management approach. Furthermore, taking into account the age and sex differences in the presymptomatic phase of AD can refine patient selection for clinical trials.

4. Conclusion

Neurodegenerative diseases representing a continuous biological disease spectrum provide an important opportunity to investigate the presymptomatic phase in the disease. MS and AD are two chronic neurodegenerative diseases with multiple stages in the disease course, including the presymptomatic phase, which is influenced by both age and sex.

In the presymptomatic phase of MS, otherwise known as RIS, women are more commonly affected than men, similar to symptomatic MS. However, in RIS, in addition to younger age, male sex is a main risk factor for symptomatic MS transition, whereas older age and male sex are among main risk factors for the direct transition between RIS and primary progressive MS. In women with RIS, pregnancy may facilitate the transition to symptomatic MS, and menopause is associated with greater brain atrophy at the time of clinical MS onset. In individuals with RIS, investigation of age, sex and hormonal differences in biomarkers can help better identify risk factors for symptomatic MS transition, predict future disease outcomes and evaluate treatment response and efficacy.

In cognitively unimpaired adults, not surprisingly, older age is the strongest risk factor for developing AD. Women are more commonly and more severely affected than men and APOEε4 positivity increases the risk of AD in women, particularly at younger ages. In the presymptomatic phase of AD, biomarkers serve as essential tools in detecting disease-specific changes decades before cognitive impairment.(79) Macroscopic structural age-dependent changes on MRI start around the fourth decade with an acceleration in worsening after 60 years of age. Interestingly, in cognitively unimpaired adults, amyloid-β PET deposition does not differ by sex, whereas tau levels in CSF and PET are higher in women than in men and sex differences seem to occur downstream with acceleration of tau burden and brain atrophy, especially in the presence of APOEε4 in women, leading to a more severe global AD pathology and cognitive impairment in women compared to men.

Women seem to be more vulnerable to AD-related pathology after menopause. The potential detrimental effects of hormone deficiency on cognitive function are reinforced by the studies on surgical menopause with abrupt disruption in ovarian hormones. In cognitively unimpaired women, PBO before 46 years of age is associated with an increased risk of dementia along with AD-like pattern of neurodegeneration and elevated amyloid-β and tau deposition, implying that women should avoid surgical menopause in the absence of malignancy or a genetic risk for ovarian cancer. The impact of menopausal hormone therapy on dementia risk lacks consensus, and hormone therapy is not recommended for reducing the risk of dementia. The decision to use hormone therapy should be shaped around the timing of menopause, type of menopause, and the presence of vasomotor symptoms, following the therapeutic window of opportunity of appropriate dose and time in a well-defined and appropriate patient population.

The ultimate goal in the management of neurodegenerative diseases such as MS and AD with long-term disease continuums is to detect and monitor disease-specific pathological changes in the presymptomatic phase, years or decades before individuals develop clinical symptoms, to intervene early and effectively. Advanced imaging, blood- and CSF-based biomarkers are instrumental in the identification and surveillance of individuals in the presymptomatic phase. Determining the influence of age and sex on the presymptomatic phases of neurodegenerative diseases with the help of biomarkers advances patient selection for clinical trials, optimization of individualized care and discovery of novel therapeutics.