Association of Self-Reported Psychological Stress with Cognitive Decline: A Systematic Review.

Psychological stress is a potential modifiable risk factor for cognitive decline. However, the extent to which self-reported psychological stress is differentially associated with decline in specific cognitive domains remains unclear. Differences may be due to heterogeneity in the aspects of psychological stress investigated, for example, neuroticism (which is linked to vulnerability to stress), perceived stress, or exposure to stressful life events. This review aims to establish the associations between these aspects of self-reported psychological stress and cognitive decline. PsychINFO, Embase and MEDLINE were searched from database inception to September 2021. Studies were included if they were observational, prospective, and if they investigated the association between self-reported psychological stress and cognitive decline in adults with a minimum mean age of 40 years at baseline. Thirty studies satisfied the inclusion criteria, with most examining neuroticism (n = 17) as a predictor of cognitive decline. Fewer examined perceived stress (n = 7) or stressful life events (n = 6). There was evidence of an association between neuroticism and cognitive decline, particularly in the domain of memory. Similarly, across studies, perceived stress was also associated with memory decline. Research investigating the relationship between stressful life events and cognitive decline had fewer outcomes to interpret. Overall, the findings highlight that memory may be particularly susceptible to high levels of neuroticism and perceived stress. We identified a lack of research into some cognitive domains, such as executive function, which should be addressed by future studies.

Associations between multidomain modifiable dementia risk factors with AD biomarkers and cognition in middle-aged and older adults.

This study aimed to determine associations between modifiable dementia risk factors (MDRF), across domains mood symptomatology, lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology, with cognition, beta-amyloid (Aß) and tau, and brain volume. Middle-aged/older adults (n=82) enrolled in a sub-study of the Healthy Brain Project completed self-report questionnaires and a neuropsychological battery. Cerebrospinal fluid levels of Aß 1-42, total tau (t-tau), and phosphorylated tau (p-tau181) (Roche Elecsys), and MRI markers of hippocampal volume and total brain volume were obtained. Participants were classified as no/single domain risk (≤1 domains) or multidomain risk (≥2 domains). Compared to the no/single domain risk group, the multidomain risk group performed worse on the Preclinical Alzheimer's Cognitive Composite (d=0.63, p=.005), and Executive Function (d=0.50, p=.016), and had increased p-tau181 (d=0.47, p=.042) and t-tau (d=0.54, p=.021). In middle-aged/older adults, multidomain MDRFs were related to increases in tau and worse cognition, but not Aß or brain volume. Findings suggest that increases in AD biomarkers are apparent in midlife, particularly for individuals with greater burden, or variety of MDRFs.

Exploring the Potential Association Between Self-Reported Psychological Stress and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Midlife: A Cross-Sectional Study.

Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-ß42, phosphorylated tau-181, total tau, or neurofilament light chain. Cohen's f2 effect sizes were small in magnitude (f2≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels of stress.

Associations of Perceived Stress and Psychological Resilience With Cognition and a Modifiable Dementia Risk Score in Middle-Aged Adults.

OBJECTIVES: Psychological stress has been proposed as a risk factor for cognitive impairment and dementia. However, it remains unclear how an individual's stress-coping ability (i.e., psychological resilience) is related to cognition. This cross-sectional study investigated whether perceived stress and psychological resilience were associated with cognition and a modifiable dementia risk score in a large community-based sample of cognitively normal adults. The moderating effect of psychological resilience was also examined. METHODS: Participants (mean age = 57 ± 7 years) enrolled in the web-based Healthy Brain Project completed the Perceived Stress Scale and the Connor-Davidson Resilience Scale. Domains of attention and working memory were assessed using the Cogstate Brief Battery (n = 1,709), and associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery (n = 1,522). Dementia risk was estimated for 1,913 participants using a modified version of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia dementia risk score, calculated using only readily modifiable dementia risk factors. RESULTS: In separate linear regression analyses adjusted for age, sex, education, and race, greater levels of perceived stress and lower levels of psychological resilience were associated with poorer performance across all cognitive domains, as well as a higher modifiable dementia risk score. Psychological resilience did not moderate the effect of perceived stress on cognition or the dementia risk score. DISCUSSION: Higher perceived stress and lower resilience were associated with poorer cognition and a greater burden of modifiable dementia risk factors. Intervention studies are required to determine if lowering stress and building resilience can mitigate cognitive deficits and reduce dementia risk.

Multidomain modifiable dementia risk factors are associated with poorer cognition in midlife.

OBJECTIVE: Studies of modifiable dementia risk factors (MDRFs) generally consider MDRFs individually, despite strong evidence that they co-occur in adult populations. In a large sample of middle-aged adults, this study aimed to determine the frequency and co-occurrence of MDRFs, spanning five domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology). The relationship between number of domains in which MDRFs were reported with cognitive performance and subjective cognitive concerns was then determined. METHOD: Middle-aged adults (n = 1,610) enrolled in the Healthy Brain Project and completed self-report surveys about their health and lifestyle. Participants also completed the Cogstate Brief Battery and the Cognitive Function Instrument, a measure of subjective ratings of cognition. Participants were classified according to number of domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology) in which they reported at least one MDRF (0-5). Age, sex, education, and ethnicity were adjusted for in analyses. RESULTS: Most individuals (66.5%) reported MDRFs in two or more domains. Compared with individuals displaying no MDRFs, individuals with MDRFs in 3-5 domains showed worse learning/working memory performance and greater subjective cognitive concerns, with the magnitude of these differences moderate-to-large (d = 0.30-0.93). Individuals displaying MDRFs in five domains also showed worse attention/psychomotor function (d = 0.58) compared to those displaying no MDRFs. CONCLUSIONS: These findings may suggest that multidomain MDRFs are highly frequent in middle-aged adults and are related to poorer cognition. This supports that modifiable dementia risk is multidimensional and raises the possibility that multidomain behavioral intervention trials in middle-aged adults may be useful to delay or prevent cognitive impairment or decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

CSF Aß42 and tau biomarkers in cognitively unimpaired Aß- middle-aged and older APOE ε4 carriers.

This study aimed to determine the relationship between the apolipoprotein E (APOE) ε4 allele and cerebrospinal fluid (CSF) and neuroimaging biomarkers of Alzheimer's disease, and cognition in cognitively unimpaired (CU) middle-aged adults (n = 82; Mage = 58.2), and in Aß- CU older adults (n = 71; Mage = 71.8). Aß- CU middle-aged ε4 carriers showed lower CSF Aß42 levels, higher levels of CSF total tau (t-tau) and neurofilament light (NfL), and poorer cognitive performance compared to noncarriers (Cohen's d: 0.30-0.56). In Aß- CU older adults, ε4 carriers also had lower CSF Aß42 levels and higher levels of CSF t-tau and p-tau181, compared to noncarriers (Cohen's d: 0.65-0.74). In both Aß- middle-aged and older adults, hippocampal and total brain volume were equivalent between ε4 carriers and noncarriers. In Aß- CU middle-aged adults, APOE ε4 is associated with decreased levels of Aß, increased tau and NfL, and poorer cognition. Similar relationships were observed in Aß- CU older adults. These results have implications for understanding clinicopathological relationships between APOE ε4 and the emergence of cognitive and biomarker abnormalities in Aß- adults.

Insomnia Symptoms and Biomarkers of Alzheimer's Disease in the Community.

BACKGROUND: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer's disease remains equivocal. OBJECTIVE: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer's disease biomarkers in a cognitively unimpaired middle-aged community sample. METHODS: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia's core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aß42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOEɛ4 genotype. RESULTS: Higher ISI score was associated with greater average levels of CSF Aß42 (per point: 30.7 pg/mL, 95% CI: 4.17-57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48-223, p = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55-192, p < 0.001). Difficulty initiating sleep was not associated with CSF Aß42, nor were insomnia features associated with p-tau181, total-tau, or NfL levels. CONCLUSION: Insomnia symptoms were associated with higher CSF Aß42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption.

The relationship between cognitive engagement and better memory in midlife.

INTRODUCTION: Engagement in cognitively stimulating work and activities may slow cognitive decline and dementia. We examined the individual and combined associations of four cognitive engagement indices (educational attainment, occupational complexity, social engagement, and cognitively stimulating leisure activities) with objective and subjective cognition. METHODS: Middle-aged adults (n = 1864) enrolled in the Healthy Brain Project completed the Cogstate Brief Battery, the Cognitive Function Instrument, and self-report questionnaires of cognitive engagement. RESULTS: Educational attainment and leisure activity engagement were individually associated with memory performance. Participants were classified based on whether they rated highly in zero to four cognitive engagement indices. Compared to participants with no indices, participants with two or more indices performed moderately better on memory. DISCUSSION: Results suggest that greater variety of cognitive engagement across different areas of life is related to better memory in midlife. Possible explanation for this relationship may be increased opportunity for enhancing cognitive reserve, but further investigations are required.

Elucidating the association between depression, anxiety, and cognition in middle-aged adults: Application of dimensional and categorical approaches.

BACKGROUND: In older adults, depressive and anxiety symptoms are associated with dementia risk, and represent a manifestation of the dementia prodrome. Understanding how these symptoms are related to cognition in midlife may inform risk models of dementia. METHODS: This study examined the relationship between depressive and anxiety symptoms, and cognition, in a sample (n= 2,657) of participants enrolled in the Healthy Brain Project. Depressive and Anxiety symptoms were assessed using the Depression Anxiety and Stress Scale, Hospital Anxiety and Depression Scale, and centre for Epidemiological Studies Depression Scale. Objective cognition was assessed using the Cogstate Brief Battery and subjective cognition assessed using the Alzheimer's disease Cooperative Study Cognitive Function Instrument. RESULTS: Somatic- and panic-related anxiety symptoms were associated significantly with poorer attention; while tension- and panic-related anxiety were associated significantly with poorer memory. Having clinically meaningful anxiety or depressive symptoms was associated with increased subjective cognitive concerns (d=-0.37). This was further increased for those with clinically meaningful anxiety and depressive symptoms (d = -1.07). LIMITATIONS: This study reports cross-sectional data, and uses a sample enriched with individuals with a family history of dementia who are therefore at a higher risk of developing dementia compared to the general population. Additionally, biological markers such as cortisol, Aß, and tau were unavailable. CONCLUSION: The results support the hypothesis that depressive and anxiety symptoms may increase risk of cognitive decline. Further, they suggest that using depression and anxiety as clinical markers may be helpful in identifying the earliest signs of cognitive decline.

Differential Effects of APOE and Modifiable Risk Factors on Hippocampal Volume Loss and Memory Decline in Aß- and Aß+ Older Adults.

BACKGROUND AND OBJECTIVES: This prospective study sought to determine the association of modifiable/nonmodifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score with hippocampal volume (HV) loss and episodic memory (EM) decline in cognitively normal (CN) older adults classified as brain ß-amyloid (Aß) negative (Aß-) or positive (Aß+). METHODS: Australian Imaging, Biomarkers and Lifestyle study participants (age 58-91 years) who completed ≥2 neuropsychological assessments and a brain Aß PET scan (n = 592) were included in this study. We computed the CAIDE risk score (age, sex, APOE ε4 status, education, hypertension, body mass index [BMI], hypercholesterolemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR; education, hypertension, BMI, hypercholesterolemia, physical inactivity) for each participant. Aß+ was classified using Centiloid >25. Linear mixed models assessed interactions between each CAIDE score, Aß group, and time on HV loss and EM decline. Age, sex, and APOE ε4 were included as separate predictors in CAIDE-MR models to assess differential associations. Exploratory analyses examined relationships between individual modifiable risk factors and outcomes in Aß- cognitively normal (CN) adults. RESULTS: We observed a significant Aß group × CAIDE × time interaction on HV loss (ß [SE] = -0.04 [0.01]; p < 0.000) but not EM decline (ß [SE] = -2.33 [9.96]; p = 0.98). Decomposition revealed a significant CAIDE × time interaction in Aß+ participants only. When modifiable/nonmodifiable CAIDE components were considered separately, we observed a significant Aß group × CAIDE-MR × time interaction on EM decline only (ß [SE] = 3.03 [1.18]; p = 0.01). A significant CAIDE-MR score × time interaction was observed in Aß- participants only. Significant interactions between APOE ε4 and age × time on HV loss and EM decline were observed in both groups. Exploratory analyses in Aß- CN participants revealed a significant interaction between BMI × time on EM decline (ß [SE] = -3.30 [1.43]; p = 0.02). DISCUSSION: These results are consistent with studies showing that increasing age and APOE ε4 are associated with increased rates of HV loss and EM decline. In Aß- CN adults, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over ∼10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group.

Association of Stress with Risk of Dementia and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

BACKGROUND: Although many studies have investigated the association between stress and risk of dementia, findings are inconsistent due to the variation in the measures used to assess stress. OBJECTIVE: We conducted a systematic review and meta-analysis to investigate the association between psychological stress (including neuroticism, stressful life events, and perceived stress) and the risk of incident dementia and mild cognitive impairment in adults. METHODS: PsycINFO, Embase, and MEDLINE were searched to October 2020 for eligible observational, prospective studies. Of the 1,607 studies screened, 26 (24 unique cohorts) were included in the qualitative analysis and 16 (15 unique cohorts) were included in the quantitative analysis. RESULTS: Across studies, higher perceived stress was significantly associated with an increased risk of mild cognitive impairment (Cases/Total N = 207/860: hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 1.03-1.38) and all-cause dementia (Cases/Total N = 203/1,882: HR = 1.44, 95% CI = 1.07-1.95). Exposure to two or more stressful life events (versus none) was significantly associated with an increased risk of all-cause dementia (Cases/Total N = 3,354/11,597: HR = 1.72, 95% CI = 1.14-2.60), while one or more stressful life events was not. Higher neuroticism was significantly associated with an increased risk of Alzheimer's disease dementia (Cases/Total N = 497/4,771: HR = 1.07, 95% CI = 1.01-1.12), but not all-cause dementia. CONCLUSION: This review suggests that psychological stress in adulthood is associated with an increased risk of dementia. Further research is needed to clarify the mechanisms underlying these associations.

Visual Memory Deficits in Middle-Aged APOEɛ4 Homozygotes Detected Using Unsupervised Cognitive Assessments.

BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. OBJECTIVE: We examined effects of ɛ4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. METHODS: HBP participants (1,000 non-carriers; 450 ɛ4 heterozygotes; 50 ɛ4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ4 heterozygotes; 31 ɛ4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. RESULTS: Greater memory impairment was observed in middle-aged ɛ4 homozygotes compared with ɛ4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. CONCLUSION: Memory impairment in ɛ4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ4 homozygosity increases with older age. APOEɛ4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships.

The Healthy Brain Project: An Online Platform for the Recruitment, Assessment, and Monitoring of Middle-Aged Adults at Risk of Developing Alzheimer's Disease.

BACKGROUND: Characterizing the earliest demonstrable cognitive decline in middle-aged adults at risk of Alzheimer's disease (AD) will allow for the better understanding of the early disease trajectory, and the provision of therapies prior to clinical symptom onset. We developed an online platform- healthybrainproject.org.au (Healthy Brain Project; HBP)- to recruit, assess, and monitor at-risk middle-aged adults. OBJECTIVE: Describe the HBP methodology and report baseline characteristics and adherence indices of participants. METHODS: Between February 2017 and August 2018, 4,000 community-based middle-aged Australian adults with a first or second-degree family history of dementia enrolled at our website (healthybrainproject.org.au). Participants were directed to complete five modules: "Basics", "Health History", "How You Feel", "How You Live", and "How You Think". Of these, 1,816 participants have received a saliva sampling kit for genetic analysis. RESULTS: Participants had a mean (SD) age of 55.5 (6.8) years, 11.8 (3.4) years of education, and annual personal income of AUD$68,830 ($35,044). Participants took 26.4 (49.7) days after enrolment to complete questionnaires and cognitive tests. Most participants were from Victoria (63%), followed by New South Wales (14%). Most participants (74%) were female and 76% identified as Caucasian. Approximately 36% of participants completed all modules (n = 1,450), and 56% (n = 2,221) completed 4 out of 5 modules. Most saliva kits (89%) had been returned. CONCLUSION: The HBP joins a handful of online registries worldwide that assess and monitor a large cohort of individuals at risk of AD. Our study extends on these efforts by focusing on midlife, where the earliest signs of cognitive and pathological changes will manifest.

Sensitivity of a Preclinical Alzheimer's Cognitive Composite (PACC) to amyloid ß load in preclinical Alzheimer's disease.

Introduction: Preclinical Alzheimer's disease (AD) is characterized by amyloid-related cognitive decline. Reduction in this decline is used to determine the efficacy of drug therapies designed to forestall the disease in preclinical AD clinical trials, measured by a Preclinical Alzheimer's Cognitive Composite (PACC). Most studies estimate rates of cognitive change by comparing cognitively normal (CN) older adults with abnormally high beta-amyloid (Aß+) to those with low levels (Aß-). However, participants of preclinical AD clinical trials must be Aß+ for entry. Therefore, we estimated the effect of very high amyloid (Aß++) and Aß+ on cognitive change over three years measured by different versions of the PACC in individuals with preclinical AD. Method: CN older adults underwent Aß neuroimaging and neuropsychological assessments over three years as part of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Three cognitive composite scores were computed: the Alzheimer's Disease Cooperative Study (ADCS)-PACC, the ADCS-PACC with no Mini-Mental State Examination (MMSE), and the z-scores of Attention, Verbal Fluency and Episodic Memory for Nondemented Older Adults (ZAVEN) composite. Results: Compared to the Aß++ group, the Aß+ group showed a slower rate of cognitive decline with the largest magnitude of difference reflected by the ADCS-PACC (d = 0.85). The ADCS-PACC excluding the MMSE and the ZAVEN also reflected a moderate to large magnitude of difference between groups (d = 0.62, d = 0.72, respectively). Conclusions: When all individuals have abnormal Aß, the level of Aß at baseline is associated with the rate of subsequent decline. The ADCS-PACC was the most sensitive composite score in showing that lower Aß is associated with a slower rate of cognitive decline; however, there are limitations to the use of the MMSE. These results provide a benchmark of comparison for preclinical AD clinical trials aiming to slow cognitive deterioration.