Introduction
Subjective Cognitive Decline (SCD) was defined as a self-experienced persistent decline of cognitive capacity in comparison with the subject’s previously normal status, during which the subject has normal age-, sex-, and education-adjusted performance on standardized cognitive tests [
1]. SCD has been shown to be associated with higher neuroradiological features similar to those seen in Alzheimer’s Disease (AD) patients, such as volume loss in hippocampal/parahippocampal areas [
2,
3] and amyloid deposition [
4]. Two meta-analyses showed that individuals with SCD are twice as likely to develop Mild Cognitive Impairment (MCI) or dementia as individuals without [
5,
6]. For these reasons, SCD is getting growing attention from clinical research as it represents a target population for the identification of individuals in the preclinical phase of AD.
SCD could also be due to non-degenerative conditions, such as normal aging, personality traits, psychiatric conditions, neurologic and medical disorders, substance use, and medication [
7].
Several studies applying multifactorial approaches found that demographic and genetic factors, such as age at onset [
1,
8], APOE ε4 genotype [
8], and cognitive reserve [
9‐
11], may influence the risk of progression from SCD to MCI and dementia.
Sex is a demographic variable which has been associated with AD: previous studies showed that two thirds of those diagnosed with AD are women [
12]. Sex seems to have a role also on SCD prevalence, as several authors described a higher proportion of women in the SCD population [
13‐
15] and a tendency for women to report more concerns associated with SCD than men [
16,
17]. However, possible relationships between sex and SCD features have not been explored so far.
In particular, we hypothesized that sex might influence cognitive reserve [
18]. Gender differences in the cognitive reserve have been previously described in AD patients, highlighting that AD women present lower education levels [
18].
However, studies about cognitive reserve contributors are from mixed-sex cohorts and did not divide their samples by sex. Therefore, whether characteristics of cognitive reserve hold for both women and men is unknown [
18].
To the best of our knowledge, no studies have analyzed the interaction between sex and cognitive reserve in SCD cohorts. In this scenario, we aimed to investigate gender differences in cognitive reserve evaluating how sex might modulate the role of cognitive reserve on SCD.
Discussion
Our study aimed to investigate gender differences in cognitive reserve evaluating how sex might modulate the role of cognitive reserve on SCD.
First of all, in our cohort, we found a greater proportion of women compared to men, in line with previous findings in larger populations [
13‐
15] and reflecting the well-known sex discrepancy in AD, since two thirds of those diagnosed with AD are women [
12]. We also showed that all considered variables in our works were different between female and male populations, supporting previous works suggesting considering sex differences in studies on cognition and SCD [
17,
33].
As a pivotal result, we focused on the difference in cognitive reserve proxies between sexes. In our cohort, premorbid intelligence (measured as TIB) and years of education were lower in women compared to men, as commonly found in the literature [
18]. In particular, we found a significant gap in premorbid intelligence between women and men with the same educational level. In other words, at constant years of education, men had higher premorbid intelligence compared to women, independently from possible confounding factors.
Secondly, we found that cognitive reserve influences the age at onset of SCD in a different manner depending on the sex of patients. Indeed, age at onset was directly associated with premorbid intelligence both in men and in women. However, in women, we found an inverse relationship between years of education and age at onset of SCD.
The direct association between premorbid intelligence and age at onset of SCD may be in line with Stern’s model of cognitive reserve, which assumes that highly intelligent or educated individuals appear to be able to better cope with the presence of a neurogenerative pathology, maintaining a normal functional level for a longer time than less intelligent or educated people [
9]. There are poor data on the relationship between cognitive reserve proxies and age at the onset of SCD. The majority of the studies focused on the role of cognitive reserve in mild cognitive impairment (MCI) and AD [
11,
34] and on the interaction between cognitive reserve and age at onset on the progression of cognitive decline. Furthermore, previous studies on SCD showed that lower cognitive reserve is associated with greater overall memory concerns [
3].
The different effect of education between women and men is a challenging issue and may be explained by a multifactorial approach. Social factors should be taken into account. Many cognitive reserve contributors are highly gendered, including education, occupation, physical activity, and social support. Most participants in studies on cognitive reserve were AD patients, and most studies on AD were conducted in the early to mid-1900s when, because of gender norms, cognitive reserve factors such as education, occupation, and physical activity were principally male [
18]. Moreover, we should consider that normal education typically ends decades before old age begins. Other experiences in adulthood and old age such as social activity [
35], conscientiousness [
36], cognitively demanding work [
37], and purpose in life [
38] could influence the late-life level of cognitive activity (roughly analogous to schooling), which has been associated with the rate of cognitive change [
39,
40]. This implies that influences on cognitive reserve vary over time, with recent experiences more influential than remote experiences such as schooling [
41].
As a consequence, we might hypothesize that education plays a different role according to gender, probably acting as a minor contributor of cognitive reserve in women, in line with current research [
41]. This could explain why years of education and premorbid intelligence are inversely related to age at onset in women in our SCD cohort, but further studies are needed to evaluate this hypothesis. However, other factors with an already known gendered effect on the brain should be taken into account.
From a biological point of view, the reported sex-specific differences may be explained, at least in part, by the role of sex hormones on brain function. Estrogen is thought to have a neuroprotective effect, and estrogen loss due to menopause might have a significant effect on cognitive decline and AD [
42].
Studies also suggested an interaction between sex and APOE ε4 as the presence of this allele seems to reduce or abolish the neuroprotective effect of estrogen [
43,
44]. However, in our sample, women had a lower prevalence of APOE ɛ4 compared to men, and we did not find any interaction between APOE ɛ4 and cognitive reserve.
Nevertheless, other genetic factors might be considered to explain sex differences in cognitive reserve. Sex commonly and substantially influences many facets of the human brain from ion channels to brain morphology [
45]. As described in previous studies, genes important in the evolution of the human brain would be expected to have sex-specific effects [
46]. Future studies including more genetic variables should be carried on in order to explore this point.
Moreover, selective differences in cognitive domain performances should be considered, as neurological bases of cognitive reserve seem to be different between women and men. In fact, it has been suggested that women present an advantage for verbal memory, which could be a form of cognitive reserve specific to females, called “memory reserve” [
47].
Finally, we could speculate that the opposite effect of education on the age of onset of SCD might reflect the heterogeneity of SCD. For instance, women might be more prone than men to SCD due to non-degenerative conditions, on which education may act differently from neurodegenerative cognitive decline. We aim to explore this hypothesis in future works including AD biomarkers and follow-up data.
As a further result, we found that sex and cognitive reserve influence the severity of cognitive complaints. First of all, the severity of complaints was higher in women compared to men. This finding is in line with previous studies on SCD, which demonstrated that women concern more than men about memory loss [
13,
16,
48]. In the men group, we found that the higher the cognitive reserve, the worse the complaint. This result is in contrast with previous studies reporting that less-educated individuals showed a higher grade of cognitive complaint [
48,
49]. This discrepancy could be due to the different cognitive reserve proxies included in our regression model. We already discussed that premorbid intelligence and years of education might contribute differently to cognitive reserve storage. Moreover, the different recruitment method should also be taken into account: in our work, memory clinic patients were included, while previous studies are community based. This distinction has been recommended also by other authors based on the evidence that demographic and neuropsychological features are different according to the recruitment method [
50].
Our work has some limitations. First, the lack of biomarkers data. As the cognitive reserve hypothesis is based on the assumption that different grade of pathology load corresponds to a different grade of cognitive decline, the estimation of grade disease by means of CSF biomarkers and functional and structural imaging may undoubtedly provide useful information. Secondly, as it is a single-center study, there may be estimator and analytical biases with regard to assessment and diagnosis procedures. Moreover, as we considered a clinic-based cohort, sampling error might be possible. Finally, due to the absence of a comparison group, we cannot describe if the relationship between cognitive reserve and sex is specific to SCD patients or if they can be detected in older adult people.
On the other hand, this study has some remarkable strengths such as the relatively large sample size and the inclusion of a great number of variables, among which genetic variables, scale for depression, two cognitive reserve proxies, and a cognitive complaints measure. Moreover, to the best of our knowledge, this is one of the first studies investigating gender differences in cognitive reserve in SCD.
In conclusion, we showed that sex and cognitive reserve interact in influencing age at onset and severity of SCD. This interaction seems to hide a high degree of complexity and, at the state of the art, it is not possible to define a complete and uniform model describing the relationship between sex and cognitive reserve in SCD. The understanding of such gendered differences and complexities is pivotal for integrating cognitive reserve into a personalized medicine approach, especially in SCD cohorts’ studies, in order to better define the risk of progression to AD and to detect candidates for future treatment options.
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