Comorbidities associated with symptoms of subjective cognitive decline in individuals aged 45 – 64

Context: Early-stage cognitive decline occurs when an individual experiences memory loss or other cognitive impairment but does not meet the criteria for Alzheimer ’ s disease (AD) or other dementias. After diagnosis of mild cognitive impairment (MCI), approximately 5 – 15 % of cases progress to dementia per year. AD and many other causes of dementia are presently incurable. Early recognition of cognitive decline can allow healthcare providers to reduce the risk of disease progression. Literature is scarce on factors that can increase the incidence of cognitive decline, especially in early ages; this is further exacerbated by di ﬃ - culty tracking the prevalence of mild cognitive symptoms. Objectives: This analysis aims to determine demographic and comorbid factors that predispose individuals to higher rates of early-stage subjective cognitive impairment in order to determine which individuals should be screened at earlier stages. Methods: We conducted a cross-sectional analysis of data

impairment cannot be explained better by other diagnoses [3,5].Thus, the true prevalence of mild cognitive decline may be hidden behind the diagnoses of other conditions, which may or may not include symptoms of cognitive impairment.This has made it difficult to conduct a comprehensive study of the comorbidities associated with mild cognitive impairment, thereby negatively impacting the ability to identify key early intervention strategies [5].
Still, many efforts have been put forth into uncovering lifestyle trends or preexisting conditions that may predispose an individual to developing cognitive impairment.The most significant factors contributing to the risk of early cognitive decline are age and genetics (the apolipoprotein 4 [APOE4] gene) [1,2,6].Regarding potentially modifiable factors, studies have found a significant connection between the development of MCI or the progression from MCI to dementia with sedentary lifestyle [7], low educational attainment [6], depression [4,8,9], diabetes [10], anemia [3], and transient ischemic attacks [3].Further, numerous social determinants of health have been associated with the development of AD and other dementias.Lower educational attainment, poor access to healthcare, and increased social isolation have all been associated with higher rates of cognitive decline [11].
Several studies have looked into differences in presentation of early-onset (usually defined as <65 years of age) vs. late-onset cognitive decline (≥65).For instance, earlyonset MCI more frequently involves difficulty with object recognition, whereas later-onset MCI often includes deficits in scene recognition [12].Moreover, when MCI progresses to AD, the early-onset group tends to experience more severe disability in cognitive functions [13].While many strides have been made to understand the general predisposing factors for early cognitive declineas well as how symptoms differ based on age of onsetliterature is scarce on comorbidities that are associated with symptoms of cognitive decline early in life.
Given the risk of initial cognitive symptoms progressing to conditions with significant functional deficits later in life, this study examined correlations between identified dementia comorbidities and subjective cognitive decline (SCD) in individuals ages 45-64 years.SCD is the selfreported presence of worsening memory loss or confusion.Our primary objective was to determine the rates of SCD occurrence among individuals within this age range overall and for those with comorbidities of diabetes, stroke, hypertension, myocardial infarction (MI), chronic heart disease, chronic kidney disease (CKD), or depression.Our secondary objective was to identify the likelihood of SCD occurrence among these comorbidities in the context of certain sociodemographic factors, as well as whether certain comorbidities were more highly associated with "severe SCD" (that is, impacting work or household tasks).To conduct this study, we utilized data from the CDC's 2017-2021 Behavioral Risk Factor Surveillance System (BRFSS).

Data source
We conducted a cross-sectional analysis of data from the 2017-2021 BRFSS, which is a yearly survey conducted by the CDC that collects data on health-related risk-behaviors, chronic health conditions, and the use of preventive services in all 50 states as well as three US territories [14].Specifically, we analyzed the data on cognitive decline utilizing Module Number 18, which focuses on the individual's ability to think, remember, and perform daily tasks.

Inclusion criteria
Inclusion of participants for this study required meeting two criteria: the first was an affirmative response to the prompt: "During the past 12 months, have you experienced confusion or memory loss that is happening more often or is getting worse?"Following an affirmative response to this prompt, we only included individuals who were 45 through 64 years of age.Responses of "don't know/not sure" or "refused" were excluded from the analysis.

Variables
To identify potential cases of severe SCD, this study identified three relevant variables within the BRFSS data.These prompts were from module number 18 (Cognitive Decline): (1) "As a result of confusion or memory loss, how often do you need assistance with these day-to-day activities?"; (2) "During the past 12 months, as a result of confusion or memory loss, how often have you given up day-to-day household activities or chores you used to do, such as cooking, cleaning, taking medications, driving, or paying bills?"; and (3) "During the past 12 months, how often has confusion or memory loss interfered with your ability to work, volunteer, or engage in social activities outside the home?".Answers of "always," "usually," "sometimes," or "rarely," to any of these questions were categorized as severe SCD, whereas answers of "never" were categorized as nonsevere SCD.
Because our objectives were to assess for SCD among individuals between the ages of 45 and 64 with certain comorbidities and the likelihood of SCD occurrence among them, we utilized the following BRFSS questions: "Has a doctor, nurse, or other health professional ever told you that you have/had (a) stroke, heart attack, hypertension, diabetes, coronary heart disease (CHD), depression, or chronic kidney disease (CKD)?"These questions were utilized to assess the prevalence of comorbidities in individuals with MCI.
Additional demographic variables extracted from the BRFSS include race/ethnicity, education level, and income level, as previous research has shown associations between these items and cognitive decline.In the BRFSS survey, race/ethnicity were self-identified by selection of a predetermined set of racial categories.

Statistical analysis
Before analysis, we applied sampling design and weighting supplied by BRFSS.First, we determined the frequency of individuals having any SCD and severe SCD among BRFSS participants and their demographic characteristics.Next, we constructed logistic regression models to determine associations, via odds ratios (ORs) and adjusted odds ratios (AORs), between any reported SCD, as well as severe SCD, by the singular diseases listed previously and the cumulative effect of multiple comorbidities among individuals ages 45 through 64.Alpha was set at 0.05 for all analyses, which were conducted in Stata 16.1 (StataCorp, LLC, College Station, TX).This study does not meet the requirement for human subjects research and therefore was not submitted for ethics review.Reporting of results adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
The majority (89.8 %) reported no SCD, which was consistent across all sociodemographics.By sex, more females (8.4 %) reported severe SCD compared to males (7.2 %).By race, American Indian/Alaskan Natives (AI/ANs) reported the highest percentage of severe SCD (16.9 %) compared to the Asian population, which reported the lowest percentage of severe SCD (5.9 %).Among people who identified as White, 7.0 % reported SCD, whereas 10.0 % of people who identified as Black reported SCD.It was found that similar numbers of individuals in each race reported SCD that did not impact their ability to work or perform household tasks (1.8-3.0 %).SCD that did not impact work or household tasks was similarly reported across income level (2.0-3.3 %) and educational attainment (2.2-3.0 %).Of the respondents making less than $10,000 yearly, 22.1 % reported severe SCD, compared to 2.7 % of individuals making more than $75,000 yearly.Similarly, 16.0 % of those who did not graduate from high school reported severe SCD, whereas only 3.4 % of individuals who graduated from college reported severe SCD (Table 1).
When investigating individual comorbidities, we found that persons with comorbidities, in comparison to those not having the condition, were significantly more likely to report SCD.Among the conditions, persons reporting depression had the highest ORs of reporting SCD (AOR: 4.45; 95 % CI: 4.06-4.87;Table 2).These findings are similar when separating the age groups into 45 to 54 and 55-64 years of age.
With regard to the association between comorbidities and self-reported severe memory loss, the only surveyed comorbidity that did not report a significant AOR was hypertension (Table 3).This result could be becauseeven though hypertension serves as a risk factor for the development of more severe conditions that were significant for increased  SCDhypertension itself has a wide range of symptoms and is frequently asymptomatic [15].Compared to those without the specified condition, again, individuals reporting depression had the highest AOR of reporting severe memory loss (AOR 2.12; 95 % CI 1.74-2.57).
The AORs for a person reporting SCD from the adjusted logistic regression model increase as the number of comorbidities they have increases.Compared to those with no comorbidities, those with one comorbidity had an AOR of 2.31 (95 % confidence interval [CI]: 1.97-2.72),those with two comorbidities had an AOR of 4.23 (95 % CI: 3.53-5.07),and those reporting 5+ comorbidities had an AOR of 12.36 (95 % CI: 8.94-17.1;Table 4).

Discussion
Our investigation showed that more than 1 in 10 US residents between the ages of 45 and 64 years reported SCDwith nearly 80 % of those identified as having severe SCD.Among all individuals with severe SCD, those who identified as AI or AN had the highest prevalence, whereas individuals identifying as Asian had the lowest.Rates of severe SCD progressively declined as participants' income and education levels rose.Further, our results showed a significant association between SCD and the prevalence of nearly all surveyed comorbidities, including diabetes, hypertension, stroke, heart attack, CHD depression, and CKD.The associations between SCD and these comorbidities were not only significant overall (aged 45-64 years) but also significant in the separated age categories of 45-54 and 55-64 years.Having multiple comorbidities also significantly increased the likelihood of reporting comorbid SCD.Interestingly, the only statistically nonsignificant value was with hypertension in reporting comorbid severe SCD.All other comorbidities reported were found to be significant in their association with severe SCD.
Previous research of earlier BRFSS data have showed similar findings of SCD [16] and its associations with comorbidities [17].The findings of Taylor et al. [17] from the 2015-2017 BRFSS showed that rates of SCD among this same age range were 10.8 %, compared to our results of 10.25 %.
Adjusted models controlled for race, income, and education.AOR, adjusted odds ratio; BRFSS, Behavioral Risk Factor Surveillance System; CI, confidence interval; OR, odds ratio.
They also found that the prevalence of SCD was significantly higher if the individual reported one of the surveyed comorbidities (heart disease, stroke, diabetes, asthma, chronic obstructive pulmonary disease [COPD], cancer, arthritis, or CKD) [17].Our paper expands on the data provided by Taylor et al. [17] by analyzing the most recent years of survey data, including the influence of the global COVID-19 pandemic on the rates of SCD.Further, we divided the age categories between very early SCD (45-54 years) and early SCD (55-64 years) for parts of our analysis to find that the connection between these comorbidities and the prevalence of SCD among these individual age categories were similarly significant.
Our data further show that lower levels of income and educational attainment lead to higher reporting of severe SCD.It is well studied that socioeconomic factors such as education and income affect healthcare for individuals, with those on the lower end of the spectrum having decreased access [18][19][20].This increases the chance of developing one of the comorbidities looked at in our research [21].However, although this association was seen with severe SCD, this relationship was not present in SCD.This could be due to the fact that severe SCD was defined in our research by "needing assistance" or "impacting work" secondary to their confusion/memory loss.While speculative, this language could have socioeconomic connotations associated with itsuch as higher income participants having paid assistance for some of their work and household tasks such that they are not in a position to notice a decline in those taskscausing a higher percentage of individuals with a lower income level/ educational attainment to report severe SCD.
Diabetes [22], stroke [23], heart attacks [24], CHD [25], and CKD [26] have all been previously associated with increased risk of cognitive decline and dementia, in alignment with our findings.Changes to brain function in diabetes (particularly Type 2 diabetes mellitus), including reduced gray matter density and impaired glucose metabolism in the cerebellar region and preorbital, prefrontal, and temporal cortex, have been linked to cognitive decline [22].Heart attacks, CHD, and CKD-associated cognitive changes have all been linked to ischemic neurological changes and small vessel disease leading to impairment in white matter integrity [23][24][25][26].Interestingly, the only nonsignificant association between a comorbidity and severe SCD is hypertension.This could be due to the high rate of individuals diagnosed with hypertension [27] and the wide variety of symptoms resultant of hypertension [28].
Among all surveyed comorbidities in the dataset, depression showed the strongest association with SCD.This implies that the development of SCD may have a higher predisposition to occur in individuals who experience depressive disorders throughout their life.Other studies have previously looked into this association, with one theory suggesting an influence to the hippocampus and other neural systems leading to vulnerability for neurodegenerative changes [29].Depression has been previously connected to increased rates of cognitive decline among older adults [29], estimating that premorbid depression nearly doubles the risk of developing dementia [4].Part of this association may be secondary to the increased molecular and physical senescence associated with severe major depressive disorder [30].An additional contributing factor could be the effect of antidepressant medications, although the connection between these medications and MCI is still being debated [31].Further, rates of depression are frequently increased with the presence of chronic comorbidities, as has been demonstrated in previous studies with diabetes [32], cardiovascular disease [33], COPD [34], and CKD [35].However, it is difficult to differentiate whether SCD has caused increased depressed mood, or whether the incidence of SCD truly results from the pathology of a depressive disorder.

Implications and recommendations
Given that SCD is affecting over 10 % of US adults aged 45 to 64 yearsespecially those with comorbidities of heart disease, stroke, diabetes, asthma, COPD, cancer, arthritis, or CKDexpanding early detection and treatment of SCD will be a key health strategy for slowing or reversing the progression of SCD to dementia or AD among this growing subpopulation.Early detection and treatment of comorbidities that are associated with increased prevalence of SCD is a crucial consideration and application of this data.Our data analysis suggests that individuals aged 45 years and over with certain comorbidities, particularly depression, should be assessed for cognitive decline.Further, the potential long-term sequela of cognitive decline with these comorbidities also indicates the need for earlier screenings and interventions for these diseases.Promotion of diet, exercise, and general wellness among the populations at risk for these diseases, before they develop, could delay the SCD associated with these comorbidities.
Even with the resolution of depressive symptoms, the DSM-5 acknowledges the potential persistence of cognitive disorders [36].In 2013, the FDA and the European Union approved the use of a vortioxetine for major depressive disorder (MDD); to date, this is the only antidepressant drug that has shown effects to cognitive functioning [9].Treatment aimed at improving cognitive symptoms has been difficult in recent years, however, due to the lack of efficacy of current medications to improve cognition [9] and the mixed results of nonpharmacological therapies for cognitive impairment [37].Future research efforts should focus on drugs with similar effects that improve cognition while treating depressive disorders.

Limitations and future research
A limitation in our research is the potential differences in how participants interpret the concept of cognitive decline; however, the BRFSS item specifically asks if the individual thinks it is progressing.Self-report of sociodemographics and comorbidities are also subject to social desirability bias, as well as potential misreporting due to the symptoms of SCD itself, or acute illnesses or exacerbations of chronic illnesses, which may manifest with self-resolving cognitive symptoms.However, BRFSS is a large, nationally representative dataset that has been reliably utilized for health reporting for many years.Additionally, acute hyperglycemic episodes have been shown to impact cognition [38], potentially confounding SCD reporting in individuals with diabetes.Future studies into episodes of SCD, controlled for factors such as glycemic control, will further elucidate the connection between diabetes and SCD.
We previously mentioned that the higher rates of SCD in individuals with depression may be secondary to antidepressant medication [31].Future study into the rates of SCD among individuals with depression, controlled for the type, dose, and length of antidepressant usage, can provide more insight into this potential connection.Additionally, it should be noted that the self-reported nature of the BRFSS questionnaire does not have the same sensitivity as neuropsychological testing.This does, instead, allow us to determine which comorbidities are associated with subclinical or potentially unrecognized MCI, but our findings should be supplemented with clinical research into diagnosable MCI in the at-risk populations.

Conclusions
Our study showed that 1 in 10 US adults between the ages of 45 and 64 years reported experiencing worsening SCD.The prevalence of SCD was significantly higher among individuals with comorbidities of diabetes, hypertension, stroke, CHD, heart attack, CKD, depression, and those having multiple comorbidities.Furthermore, SCD was more likely to be reported at lower socioeconomic statuses, at lower levels of educational attainment, and among AI/AN individuals.
Insight into groups that are most at risk for development of SCD allows healthcare providers to institute screening and treatment options earlier, including high-risk individuals aged 45-54 years.Further, physician recommendations of a healthy diet, exercise, and general wellness of populations at risk for these diseases, before they develop or progress, could delay the SCD associated with these comorbidities.Providing patient education on the association between various comorbid conditions and the development of SCD can improve compliance with medication and other therapeutics, such as lifestyle changes.This can allow them to slow or reverse the progression of SCD to AD or other types of dementia.
Research ethics: This study does not meet the requirements of human subject research and thus was not submitted to ethics review.This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.Informed consent: Not applicable.

Table  :
Sociodemographics of the sample by reported subjective cognitive decline (SCD).

Table  :
Associations of comorbidities and self-reported cognitive decline within the - BRFSS.

Table  :
Associations of comorbidities and severe memory loss within the - BRFSS.

Table  :
Associations between reporting subjective cognitive decline and having multiple comorbidities among individuals aged - years from the - BRFSS.