Perceived Stress, Blood Biomarkers, and Cognitive Functioning in Older Adults.

INTRODUCTION: There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline. METHODS: This study consists of 1118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time. RESULTS: The interaction of stress, NfL concentration, and time was statistically significant on global cognition ( ß = -0.064 [SE = 0.028], p = .023) and on episodic memory ( ß = -0.097 [SE = 0.036], p = .007). CONCLUSIONS: Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce the rate of cognitive decline in individuals with high concentrations of NfL.

External validation of dementia prediction models in Black or African American and White older adults: A longitudinal population-based study in the United States.

INTRODUCTION: Identifying people at high risk of Alzheimer's disease (AD) dementia allows for timely intervention, which, if successful, will result in preventing or delaying the onset of the disease. METHODS: Utilizing data from the Chicago Health and Aging Project (CHAP; n = 2130), we externally evaluated four risk-prediction models for AD dementia, including Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), Brief Dementia Screening Indicator (BDSI), and Dementia Risk Score (DRS), in Black or African American and White adults. RESULTS: BDSI had the highest discriminate abilities for AD dementia (c-statistics of 0.79 in Black and 0.77 in White adults), followed by ANU-ADRI, within the age range and follow-up period of the original development cohort. CAIDE had the lowest discriminating power (c-statistic ≤0.55). With increasing follow-up periods (i.e., 10-15 years), the discrimination abilities for all models declined. DISCUSSION: Because of racial disparities in AD dementia and longer preclinical and prodromal stages of disease development, race-specific models are needed to predict AD risk over 10 years. HIGHLIGHTS: Utilizing risk-prediction models to identify individuals at higher risk of Alzheimer's disease (AD) dementia could benefit clinicians, patients, and policymakers. Clinicians could enroll high-risk individuals in clinical trials to test new risk-modifiable treatments or initiate lifestyle modifications, which, if successful, would slow cognitive decline and delay the onset of the disease. Current risk-prediction models had good discriminative power during the first 6 years of follow-up but decreased with longer follow-up time. Acknowledging the longer preclinical phase of AD dementia development and racial differences in dementia risk, there is a need to develop race-specific risk-prediction models that can predict 10 or 20 years of risk for AD and related dementias.

The structural and social determinants of Alzheimer's disease related dementias.

INTRODUCTION: The projected growth of Alzheimer's disease (AD) and AD-related dementia (ADRD) cases by midcentury has expanded the research field and impelled new lines of inquiry into structural and social determinants of health (S/SDOH) as fundamental drivers of disparities in AD/ADRD. METHODS: In this review, we employ Bronfenbrenner's ecological systems theory as a framework to posit how S/SDOH impact AD/ADRD risk and outcomes. RESULTS: Bronfenbrenner defined the "macrosystem" as the realm of power (structural) systems that drive S/SDOH and that are the root cause of health disparities. These root causes have been discussed little to date in relation to AD/ADRD, and thus, macrosystem influences, such as racism, classism, sexism, and homophobia, are the emphasis in this paper. DISCUSSION: Under Bronfenbrenner's macrosystem framework, we highlight key quantitative and qualitative studies linking S/SDOH with AD/ADRD, identify scientific gaps in the literature, and propose guidance for future research. HIGHLIGHTS: Ecological systems theory links structural/social determinants to AD/ADRD. Structural/social determinants accrue and interact over the life course to impact AD/ADRD. Macrosystem is made up of societal norms, beliefs, values, and practices (e.g., laws). Most macro-level determinants have been understudied in the AD/ADRD literature.

Prospective associations of interleukin-6 and APOE allele with cognitive decline in biracial community-dwelling older adults: The Chicago Health and Aging Project (CHAP).

INTRODUCTION: It is unclear whether inflammation, that is, high interleukin-6 (IL-6) levels, and genetic risk, that is, apolipoprotein E (APOE) ε4 allele, have a compounding effect on cognitive decline (CD). METHODS: We analyzed a subset of participants from the longitudinal cohort study, Chicago Health and Aging Project, comprising 1120 biracial community-dwelling older adults (60% Black and 62% women), and mean follow-up = 6.4 years. We ran adjusted mixed-effects models on2 longitudinal CD. RESULTS: In APOE ε4 carriers, higher serum IL-6 was not associated with the rate of CD (ß = -0.0091 [standard deviation (SD) = 0.0165, p = 0.5800]). Conversely, in non-ε4 carriers, compared to the lower tertile, those with the upper tertile of serum IL-6 levels experienced significantly accelerated CD (ß = -0.0257 [SD = 0.0084, p = 0.0023]). DISCUSSION: Even without the largest genetic risk factor for late-onset Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), elevated serum IL-6 still accelerate the rate of CD in non-APOE ε4 carriers. Hence, interventions ameliorating inflammation may prevent AD/ADRD. Highlights: Interleukin-6 (IL-6) and the apolipoprotein E (APOE) ε4 allele have been separately associated with an increased risk for cognitive decline, but their interaction remains unclear.In ε4 carriers, IL-6 was not associated with cognitive decline. However, even without the biggest genetic risk factor for Alzheimer's disease (AD), that is, APOE ε4, elevated serum IL-6 still could confer accelerated rate of cognitive decline, with a detrimental effect half of that imposed by APOE ε4 alone.We found no racial differences in these associations.These findings contribute complementary evidence on non-APOE ε4-dependent and non-AD biological pathways through which cognitive decline can still be accelerated in non-APOE ε4 carriers and highlight a specific subgroup of older adults who are at a higher risk of AD and thus may benefit from anti-inflammatory interventions.

Aerobic Exercise, Training Dose, and Cardiorespiratory Fitness: Effects and Relationships with Resting Plasma Neurotrophic Factors in Alzheimer's Dementia.

Background: Vascular health is increasingly recognized for its roles in the pathogenesis and progression of Alzheimer's disease (AD). The objective of this study was to investigate effects of exercise training, dose, and cardiorespiratory fitness (CRF) on neurotrophic factors in community-dwelling, older adults with mild-to-moderate AD dementia. Methods: This was a pilot blood ancillary study of the FIT-AD trial. Participants in the parent study were randomized to 6-month aerobic exercise (AEx) or stretching control. For this ancillary study, resting plasma brain-derived neurotrophic factor (BDNF), irisin, fibroblast growth factor-21 (FGF-21), and insulin-like growth factor-1 (IGF-1) biomarkers were assessed at baseline, 3, and 6 months. Estimates of within- and between-group effect sizes were calculated (Cohen's d). Relationships of biomarker change with dose and CRF change were explored with multivariable linear regression and repeated measures correlations. Results: The sample (n = 26, 18 AEx/8 stretching) averaged 77.6 ± 6.9 years old, with the majority being male (65.4%), and non-Hispanic White (92.3%); between-group effect sizes were generally small except for irisin (d = -0.44)), AEx group relative to stretching group. Associations of dose and changes in CRF with changes in neurotrophic biomarker were weak (r2 ≤ 0.025). Conclusions: The effects of exercise on BDNF, irisin, IGF-1, and FGF-21 were heterogeneous in AD. Our findings need validation in future, adequately powered exercise studies in AD.

Biomarkers of glucose homeostasis as mediators of the relationship of body mass index and waist circumference with COVID-19 outcomes among postmenopausal women: The Women's Health Initiative.

BACKGROUND & AIMS: Systematic reviews, meta-analyses and Mendelian randomization studies suggest that cardiometabolic diseases may be associated with COVID-19 risk and prognosis, with evidence implicating insulin resistance (IR) as a common biological mechanism. As driving factors for IR, we examined body mass index (BMI) and waist circumference (WC) among postmenopausal women in association with COVID-19 outcomes (positivity and hospitalization), and the role of glucose homeostasis as a mediator of this relationship. METHODS: Associations of BMI and WC at baseline (1993-1998) with COVID-19 outcomes collected at Survey 1 (June-December, 2020) and/or Survey 2 (September-December, 2021) were evaluated among 42,770 Women's Health Initiative (WHI) participants (baseline age: 59.36 years) of whom 16,526 self-reported having taken ≥1 COVID-19 test, with 1242 reporting ≥1 positive COVID-19 test and 362 reporting ≥1 COVID-19 hospitalization. We applied logistic regression and causal mediation analyses to sub-samples with available fasting biomarkers of glucose homeostasis (glucose, insulin, Homeostatic Model Assessment for Insulin Resistance, Homeostasis Model Assessment for ß-cell function, Quantitative Insulin-sensitivity Check Index, Triglyceride-Glucose index (TyG)) at baseline, whereby 57 of 759 reported COVID-19 test positivity and 23 of 1896 reported COVID-19 hospitalization. RESULTS: In fully adjusted models, higher BMI, WC and TyG were associated with COVID-19 test positivity and hospitalization. Glucose concentrations mediated associations of BMI and WC with COVID-19 positivity, whereas TyG mediated BMI and WC's associations with COVID-19 hospitalization. CONCLUSIONS: Obesity and central obesity markers collected an average of 24 years prior were associated with COVID-19 outcomes among postmenopausal women. Glucose concentration and TyG partly mediated these associations.