Association of Changes in C-Reactive Protein Level Trajectories Through Early Adulthood With Cognitive Function at Midlife: The CARDIA Study.

BACKGROUND AND OBJECTIVES: Late-life inflammation has been linked to dementia risk and preclinical cognitive decline, but less is known about early adult inflammation and whether this could influence cognition in midlife. We aimed to identify inflammation levels through early adulthood and determine association of these trajectories with midlife cognition. METHODS: We used data from the Coronary Artery Risk Development in Young Adults study to identify inflammation trajectories (C-reactive protein [CRP] level <10 mg/L) over 18 years through early adulthood (age range 24-58) in latent class analysis and to assess associations with cognition 5 years after the last CRP measurement (age range 47-63). Six cognitive domains were evaluated from tests of verbal memory, processing speed, executive function, verbal and category fluency, and global cognition; poor cognitive performance was defined as a decline of ≥1 SD less than the mean on each domain. The primary outcome was poor cognitive performance. Logistic regression was used to adjust for demographics, smoking, alcohol use, physical activity, and APOE 4 status. RESULTS: Among 2,364 participants, the mean (SD) age was 50.2 (3.5) years; 55% were female, and 57% were White. Three CRP trajectories emerged over 18 years: lower stable (45%), moderate/increasing (16%), and consistently higher (39%). Compared with lower stable CRP, both consistently higher (adjusted odds ratio [aOR] 1.67, 95% CI 1.23-2.26) and moderately/increasing (aOR 2.04, 95% CI 1.40-2.96) CRP had higher odds of poor processing speed; consistently higher CRP additionally had higher odds of poor executive function (aOR 1.36, 95% CI 1.00-1.88). For memory (moderately/increasing aOR 1.36, 95% CI 1.00-1.88; consistently higher aOR 1.18, 95% CI 0.90-1.54), letter fluency (moderately/increasing aOR 1.00, 95% CI 0.69-1.43; consistently higher aOR 1.05, 95% CI 0.80-1.39), category fluency (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), or global cognition (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), no association was observed. DISCUSSION: Consistently higher or moderate/increasing inflammation starting in early adulthood may lead to worse midlife executive function and processing speed. Study limitations include selection bias due to loss to follow-up and reliance on CRP as the only inflammatory marker. Inflammation is important for cognitive aging and may begin much earlier than previously known.

Cognitive function and bladder health among midlife adult women in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

OBJECTIVE: The aim of this study was to examine whether different aspects of women's cognitive function are associated with lower urinary tract symptoms (LUTS) and their impact. METHODS: In 2010-2011, women aged 42 to 57 years in the Coronary Artery Risk Development in Young Adults study completed different tests of cognitive function, including the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop test. Two years later, data on LUTS and their impact were collected. LUTS/impact, a four-level composite variable ranging from bladder health to mild, moderate, and severe LUTS/impact, was regressed on each cognitive test separately, as well as a cognitive function composite variable. The analytic sample was composed of 1,021 women with complete data. RESULTS: When adjusting for sociodemographic variables (age, race, education) and gynecologic/obstetric variables (parity, menopausal status, hysterectomy, hormonal use), better performance on the cognitive function composite and Digit Symbol Substitution Test were both associated with lower odds of membership to a more severe LUTS/impact category (odds ratio, 0.90 [95% confidence interval, 0.83-0.98] and 0.89 [95% confidence interval, 0.82-0.97], respectively). These associations became nonsignificant when additionally adjusting for mechanisms that might explain an association between cognitive function and LUTS/impact, including health behaviors and health conditions that may covary with cerebral and peripheral vascular health and cognitive function. CONCLUSIONS: In this sample of midlife adult women, a modest association was found between better cognitive function and lower likelihood of LUTS/impact. Longitudinal studies are needed to further investigate the association between cognitive function and LUTS/impact, as well as potential explanatory mechanisms, particularly as women age and cognitive function varies to a greater degree.

Snoring and risk of dementia: a prospective cohort and Mendelian randomization study.

STUDY OBJECTIVES: The association between snoring, a very common condition that increases with age, and dementia risk is controversial. We aimed to investigate the observational and causal relationship between snoring and dementia, and to elucidate the role of body mass index (BMI). METHODS: Using data from 451,250 participants who were dementia-free at baseline, we examined the association between self-reported snoring and incident dementia using Cox proportional-hazards models. Causal relationship between snoring and Alzheimer's disease (AD) was examined using bidirectional two-sample Mendelian randomization (MR) analysis. RESULTS: During a median follow-up of 13.6 years, 8,325 individuals developed dementia. Snoring was associated with a lower risk of all-cause dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.89 to 0.98) and AD (HR 0.91; 95% CI 0.84 to 0.97). The association was slightly attenuated after adjusting for BMI, and was stronger in older individuals, APOE ε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD, however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI. CONCLUSIONS: The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD. Increased attention should be paid to reduced snoring and weight loss in older adults as potential early indicators of dementia risk.

Psychiatric Disorders Are Common Among Older US Veterans Prior to Traumatic Brain Injury.

OBJECTIVE: To estimate the impact of traumatic brain injury (TBI) on prevalence of posttraumatic stress disorder (PTSD), depression, and alcohol and substance use disorders. SETTING: A random sample of Veteran's Health Administration data. PARTICIPANTS: A total of 14 116 veterans aged ≥55 with incident late-life TBI between October 1, 1999, and September 31, 2021, were matched 1:3 on age and TBI date to 42 678 veterans without TBI. DESIGN: Retrospective cohort study. MAIN MEASURES: PTSD, depression, and alcohol and substance use disorders were identified using diagnostic codes. Participants were censored after the first diagnosis during the year before and the year after the TBI or matched date. Prevalence rates of PTSD, depression, alcohol, and substance use disorders were compared before and after incident TBI or matched date using Poisson regression. RESULTS: Pre-TBI prevalence rates of disorders were higher among those with TBI relative to those without TBI. Pre-TBI PTSD prevalence rates (per 1000 person-years) were 126.3 (95% CI, 120.2-132.4) compared to 21.5 (95% CI, 20.1-22.9) in the non-TBI cohort. In adjusted models, TBI was not associated with an increase in the prevalence of any of the studied disorders. CONCLUSIONS: Prevalence rates of depression, PTSD, and alcohol and substance use disorders were 5 to 10 times higher among older veterans before incident TBI. We did not observe an increase in the prevalence of these disorders after incident TBI. Older veterans with these disorders may be at increased risk for TBI.

Long-Term Depressive Symptom Trajectories and Midlife Cognition: The CARDIA Study.

BACKGROUND AND OBJECTIVES: The nature of associations between depressive symptoms and cognition early in the life course remains unclear, and racial differences in these associations are not well characterized. The aim of this study was to examine the relationship between trajectories of depressive symptom over 20 years, beginning in young adulthood, and cognitive functions in middle-age among Black and White adults. METHODS: We used prospective data from participants of the Coronary Artery Risk Development in Young Adults Study. Depressive symptoms were measured at 5 study visits between 1990 and 2010 using the Center for Epidemiologic Studies Depression scale. We used latent class group-based modeling to identify 4 trajectories: "persistently low," "persistently medium," "medium decreasing," and "high increasing" depressive symptoms. In 2015, cognitive function was measured using the Digit Symbol Substitution Test (DSST), Stroop test (reverse coded), and Rey Auditory-Verbal Learning Test (RAVLT).We excluded participants who missed the cognitive battery or had no depressive symptoms measurements, resulting in a total of 3,117 participants. All cognitive tests were standardized, and linear regression was used to relate depressive trajectories with 2015 cognitive functions. RESULTS: The mean [SD] baseline age was 30.1 [3.6] years, and 57% were female. The associations between depressive symptoms and cognition significantly differed by race (p < 0.05). Among Black individuals, compared with having "persistently low," having "medium decreasing," "persistently medium," or "high increasing" depressive symptoms were associated with worse verbal memory, processing speed, and executive function scores (RAVLT persistently medium vs low: ß = -0.30, 95% CI -0.48 to -0.12; and high increasing vs low: ß = -0.49, 95% CI -0.70 to -0.27; DSST persistently medium vs low: ß = -0.28, 95% CI -0.47 to -0.09; and high increasing vs low: ß = -0.64, 95% CI -0.87 to -0.42; Stroop persistently medium vs low: ß = -0.46, 95% CI -0.70 to -0.23; and high increasing vs low: ß = -0.76, 95% CI -1.04 to -0.47). Associations were slightly weaker among White individuals, but we still found that having 'high increasing' depressive symptoms was associated with worse verbal memory and processing speed scores (high increasing vs low: ß = -0.38, 95% CI -0.61 to -0.15; and ß = -0.40, 95% CI -0.63 to -0.18, respectively). DISCUSSION: Prolonged exposure to elevated depressive symptoms beginning in young adulthood may result in worse cognitive function over midlife. This association was stronger among Black adults.

The Role of Genomic-Informed Risk Assessments in Predicting Dementia Outcomes.

Importance: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health. Objective: To develop a genomic-informed risk assessment composed of family history, genetic, and clinical risk factors and, in turn, evaluate how the risk assessment predicted incident dementia. Design: This longitudinal study included data from two clinical case-control cohorts with an average of 6.6 visits. Secondary analyses were conducted from July 2023 - March 2024. Setting: Data were previously collected across multiple US locations from 1994 to 2023. Participants: Older adults aged 55+ with whole-genome sequencing and dementia-free at baseline. Exposures: An additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, APOE genotype, and an AD polygenic risk score. Main Outcomes and Measures: The risk of progression to all-cause dementia was evaluated using Cox-proportional hazard models (hazard ratios with 95% confidence intervals [OR 9%CI]). Results: A total of 3,429 older adults were included (aged 75 ± 7 years; 59% female; 75% non-Latino White, 15% Black, 5.2% Latino, 3.6% other, and 0.4% Asian; 27% MCI), with 751 participants progressing to dementia. The most common high-risk indicator was a family history of dementia (56%), followed by APOE*ε4 genotype (36%), high mCAIDE score (34%), and high AD-PRS (11%). Most participants had at least one high-risk indicator, with 39% having one, 32% two, 9.8% three, and 1% four. The presence of 1, 2, 3, or 4 risk indicators was associated with a doubling (HR = 1.72, CI: 1.34-2.22, p = 2.5e-05), tripling (HR = 3.09, CI: 2.41-3.95, p = 4.4e-19), quadrupling (HR = 4.46, CI: 3.34-5.94, p = 2.2e-24), and a twelvefold increase (HR = 12.15, CI: 7.33-20.14, p = 3.2e-22) in dementia risk. Conclusion & Relevance: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.

Modifiable risk factors, APOE and risk of Alzheimer disease: one size does not fit all.

Introduction: Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities. Methods: We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in NACC and ADNI, and assessed their interaction with APOE . Results: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the APOE *ε4 risk effect and attenuated the APOE *ε2 protective effect. Discussion: Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health.

Development and validation of the Michigan Chronic Disease Simulation Model (MICROSIM).

Strategies to prevent or delay Alzheimer's disease and related dementias (AD/ADRD) are urgently needed, and blood pressure (BP) management is a promising strategy. Yet the effects of different BP control strategies across the life course on AD/ADRD are unknown. Randomized trials may be infeasible due to prolonged follow-up and large sample sizes. Simulation analysis is a practical approach to estimating these effects using the best available existing data. However, existing simulation frameworks cannot estimate the effects of BP control on both dementia and cardiovascular disease. This manuscript describes the design principles, implementation details, and population-level validation of a novel population-health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP-COG) study of the effect of BP levels over the life course on dementia and cardiovascular disease. MICROSIM is an agent-based Monte Carlo simulation designed using computer programming best practices. MICROSIM estimates annual vascular risk factor levels and transition probabilities in all-cause dementia, stroke, myocardial infarction, and mortality in a nationally representative sample of US adults 18+ using the National Health and Nutrition Examination Survey (NHANES). MICROSIM models changes in risk factors over time, cognition and dementia using changes from a pooled dataset of individual participant data from 6 US prospective cardiovascular cohort studies. Cardiovascular risks were estimated using a widely used risk model and BP treatment effects were derived from meta-analyses of randomized trials. MICROSIM is an extensible, open-source framework designed to estimate the population-level impact of different BP management strategies and reproduces US population-level estimates of BP and other vascular risk factors levels, their change over time, and incident all-cause dementia, stroke, myocardial infarction, and mortality.

Association of Plasma Amyloid-ß and Dementia Among Black and White Older Adults.

Background: Plasma amyloid-ß (Aß) has emerged as an important tool to detect risks of Alzheimer's disease and related dementias, although research in diverse populations is lacking. Objective: We compared plasma Aß42/40 by race with dementia risk over 15 years among Black and White older adults. Methods: In a prospective cohort of 997 dementia-free participants (mean age 74±2.9 years, 55% women, 54% Black), incident dementia was identified based on hospital records, medication, and neurocognitive test over 15 years. Plasma Aß42/40 was measured at Year 2 and categorized into low, medium, and high tertile. We used linear regression to estimate mean Aß42/40 by race and race-stratified Cox proportional hazards models to assess the association between Aß42/40 tertile and dementia risk. Results: Black participants had a lower age-adjusted mean Aß 42/40 compared to White participants, primarily among APOE ɛ4 non-carriers (Black: 0.176, White: 0.185, p = 0.035). Among Black participants, lower Aß 42/40 was associated with increased dementia risk: 33% in low (hazard ratios [HR] = 1.77, 95% confidence interval 1.09-2.88) and 27% in medium tertile (HR = 1.67, 1.01-2.78) compared with 18% in high Aß 42/40 tertile; Increased risks were attenuated among White participants: 21% in low (HR = 1.43, 0.81-2.53) and 23% in medium tertile (HR = 1.27, 0.68-2.36) compared with 15% in high Aß 42/40 tertile. The interaction by race was not statistically significant. Conclusions: Among community-dwelling, non-demented older adults, especially APOE ɛ4 non-carriers, Black individuals had lower plasma Aß 42/40 and demonstrated a higher dementia risk with low Aß42/40 compared with White individuals.

Incidence of Traumatic Brain Injury in a Longitudinal Cohort of Older Adults.

Importance: Traumatic brain injury (TBI) occurs at the highest rate in older adulthood and increases risk for cognitive impairment and dementia. Objectives: To update existing TBI surveillance data to capture nonhospital settings and to explore how social determinants of health (SDOH) are associated with TBI incidence among older adults. Design, Setting, and Participants: This nationally representative longitudinal cohort study assessed participants for 18 years, from August 2000 through December 2018, using data from the Health and Retirement Study (HRS) and linked Medicare claims dates. Analyses were completed August 9 through December 12, 2022. Participants were 65 years of age or older in the HRS with survey data linked to Medicare without a TBI prior to HRS enrollment. They were community dwelling at enrollment but were retained in HRS if they were later institutionalized. Exposures: Baseline demographic, cognitive, medical, and SDOH information from HRS. Main Outcomes and Measures: Incident TBI was defined using inpatient and outpatient International Classification of Diseases, Ninth or Tenth Revision, diagnosis codes received the same day or within 1 day as the emergency department (ED) visit code and the computed tomography (CT) or magnetic resonance imaging (MRI) code, after baseline HRS interview. A cohort with TBI codes but no ED visit or CT or MRI scan was derived to capture diagnoses in nonhospital settings. Descriptive statistics and bivariate associations of TBI with demographic and SDOH characteristics used sample weights. Fine-Gray regression models estimated associations between covariates and TBI, with death as a competing risk. Imputation considering outcome and complex survey design was performed by race and ethnicity, sex, education level, and Area Deprivation Index percentiles 1, 50, and 100. Other exposure variables were fixed at their weighted means. Results: Among 9239 eligible respondents, 5258 (57.7%) were female and 1210 (9.1%) were Black, 574 (4.7%) were Hispanic, and 7297 (84.4%) were White. Mean (SD) baseline age was 75.2 (8.0) years. During follow-up (18 years), 797 (8.9%) of respondents received an incident TBI diagnosis with an ED visit and a CT code within 1 day, 964 (10.2%) received an incident TBI diagnosis and an ED code, and 1148 (12.9%) received a TBI code with or without an ED visit and CT scan code. Compared with respondents without incident TBI, respondents with TBI were more likely to be female (absolute difference, 7.0 [95% CI, 3.3-10.8]; P < .001) and White (absolute difference, 5.1 [95% CI, 2.8-7.4]; P < .001), have normal cognition (vs cognitive impairment or dementia; absolute difference, 6.1 [95% CI, 2.8-9.3]; P = .001), higher education (absolute difference, 3.8 [95% CI, 0.9-6.7]; P < .001), and wealth (absolute difference, 6.5 [95% CI, 2.3-10.7]; P = .01), and be without baseline lung disease (absolute difference, 5.1 [95% CI, 3.0-7.2]; P < .001) or functional impairment (absolute difference, 3.3 [95% CI, 0.4-6.1]; P = .03). In adjusted multivariate models, lower education (subdistribution hazard ratio [SHR], 0.73 [95% CI, 0.57-0.94]; P = .01), Black race (SHR, 0.61 [95% CI, 0.46-0.80]; P < .001), area deprivation index national rank (SHR 1.00 [95% CI 0.99-1.00]; P = .009), and male sex (SHR, 0.73 [95% CI, 0.56-0.94]; P = .02) were associated with membership in the group without TBI. Sensitivity analyses using a broader definition of TBI yielded similar results. Conclusions and Relevance: In this longitudinal cohort study of older adults, almost 13% experienced incident TBI during the 18-year study period. For older adults who seek care for TBI, race and ethnicity, sex, and SDOH factors may be associated with incidence of TBI, seeking medical attention for TBI in older adulthood, or both.

Effect of Population-Level Blood Pressure Treatment Strategies on Cardiovascular and Cognitive Outcomes.

BACKGROUND: The large and increasing number of adults living with dementia is a pressing societal priority, which may be partially mitigated through improved population-level blood pressure (BP) control. We explored how tighter population-level BP control affects the incidence of atherosclerotic cardiovascular disease (ASCVD) events and dementia. METHODS: Using an open-source ASCVD and dementia simulation analysis platform, the Michigan Chronic Disease Simulation Model, we evaluated how optimal implementation of 2 BP treatments based on the Eighth Joint National Committee recommendations and SPRINT (Systolic Blood Pressure Intervention Trial) protocol would influence population-level ASCVD events, global cognitive performance, and all-cause dementia. We simulated 3 populations (usual care, Eighth Joint National Committee based, SPRINT based) using nationally representative data to annually update risk factors and assign ASCVD events, global cognitive performance scores, and dementia, applying different BP treatments in each population. We tabulated total ASCVD events, global cognitive performance, all-cause dementia, optimal brain health, and years lived in each state per population. RESULTS: Optimal implementation of SPRINT-based BP treatment strategy, compared with usual care, reduced ASCVD events in the United States by ≈77 000 per year and produced 0.4 more years of stroke- or myocardial infarction-free survival when averaged across all Americans. Population-level gains in years lived free of ASCVD events were greater for SPRINT-based than Eighth Joint National Committee-based treatment. Survival and years spent with optimal brain health improved with optimal SPRINT-based BP treatment implementation versus usual care: the average patient with hypertension lived 0.19 additional years and 0.3 additional years in optimal brain health. SPRINT-based BP treatment increased the number of years lived without dementia (by an average of 0.13 years/person with hypertension), but increased the total number of individuals with dementia, mainly through more adults surviving to advanced ages. CONCLUSIONS: Tighter BP control likely benefits most individuals but is unlikely to reduce dementia prevalence and might even increase the number of older adults living with dementia.

The Drug Burden Index Is Associated With Measures of Cognitive Function Among Older Adults in the Health, Aging, and Body Composition Study.

BACKGROUND: Anticholinergic and sedative medications affect cognition among older adults. The Drug Burden Index (DBI) is a validated measure of exposure to these medications, with higher DBI scores indicating higher drug burden. This ancillary analysis investigated the association between DBI and cognition assessed by the Modified Mini-Mental State Examination (3MS) and the Digit Symbol Substitution Test (DSST). METHODS: The Health, Aging, and Body Composition Study was a prospective study of community-dwelling adults aged 70-79 years at enrollment. Using data from years 1, 5, and 10, DBI was calculated using medication data per participant. Linear mixed modeling was used to assess cross-sectional and longitudinal effects of DBI on 3MS and DSST. Adjusted models included biological sex, race, education level, APOE status, and death. Sensitivity analyses included testing the strength of the associations for each year and testing attrition due to death as a possible confounding factor via Cox-Proportional Hazard models. RESULTS: After adjustment, DBI was inversely associated with 3MS and DSST scores. These associations became stronger in each subsequent year. Neither DBI at year 1 nor within-person change in DBI were predictive of longitudinal declines in either cognitive measure. Sensitivity analyses indicated that DBI, 3MS, and DSST were associated with a greater risk of attrition due to death. CONCLUSIONS: Results suggest that in years when older adults had a higher DBI scores, they had significantly lower global cognition and slower processing speed. These findings further substantiate the DBI as a useful pharmacological tool for assessing the effect of medication exposure.

Trajectories in depressive symptoms and midlife brain health.

Depressive symptoms may either be a risk factor or prodromal to dementia. Investigating this association in midlife may help clarify the role of depression in cognitive aging. We aimed to identify trajectories in depressive symptoms in early to mid-life and related cognitive and brain outcomes in midlife. This study includes 3944 Black and White participants (ages 26-45 years at baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with 20 years of follow-up. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression scale at five time points over 20 years. Growth mixture modeling (GMM) was used to identify depressive symptom trajectories. Participants completed a neuropsychological battery 20 years after baseline, including the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment (MoCA), and category and letter fluency tests. A sub-sample of participants (n = 662) underwent brain magnetic resonance imaging (MRI) to characterize gray matter volumes and white matter hyperintensities (WMHs). We identified four classes of depressive symptom trajectories: a "declining" class (n = 286, 7.3%) with initially high symptoms and subsequent decline, a class with consistently high symptoms ("steady high"; n = 264, 6.7%), a class with late increases in symptoms ("increasing"; n = 277, 7%), and a class with consistently low symptoms ("steady low"; n = 3117, 79.0%). The steady high and the increasing classes had poorer performance on all cognitive tests, while the declining class had poorer performance on the DSST, verbal fluency, and MoCA. Compared to the steady low symptom class, the steady high class had lower volumes in the entorhinal cortex (ß: -180.80, 95% CI: -336.69 to -24.91) and the amygdala (ß: -40.97, 95% CI: -74.09 to -7.85), the increasing class had more WMHs (ß: 0.55, 95% CI: 0.22 to 0.89), and the declining class was not significantly different in any brain measures. Trajectories in depressive symptoms in young to mid-adulthood show distinct cognitive and brain phenotypes in midlife. Steady high depressive symptoms may represent a group that is at risk for dementia, whereas increasing symptoms in midlife may be associated with white matter damage.

The Association Between Cognitive Reserve and Cognitive Trajectories Among Older Adults.

Background and Objectives: Prior studies on cognitive reserve (CR) and cognitive trajectories are limited and have had conflicting results. Furthermore, most studies have used a single measure of CR that may not reflect a comprehensive exposure. The objective of this study is to determine the impact of individual and composite CR measures on cognitive decline over a 6-year period. Research Design and Methods: We studied 55,340 participants from 16 European countries, aged 50 and older, who participated in the Survey of Health, Aging, and Retirement in Europe. We used cognitive measures (including immediate memory, delayed memory, verbal fluency, and numeracy) and 3 CR factors (education, occupation, and cognitive activities) collected in 4 waves from 2011 to 2017. Structural equation modeling was used to construct the composite CR score, analyzed as tertile. Linear mixed-effect models were used to examine the study aims. Results: At baseline, the highest composite CR tertile was associated with a higher cognition score than the middle and lowest CR tertiles (ß: -0.28, 95% confidence interval [CI]: -0.29 to -0.26; ß: -0.71, 95% CI: -0.72 to -0.70, respectively), as well as for all individual cognitive domains. At longitudinal results, compared with the lowest CR, the highest but not the middle CR tertile demonstrated a slower 6-year decline in global cognition (ß: -0.02, 95 % CI: -0.03 to -0.01), as well as in all cognitive domains (p < .05). Discussion and Implications: A composite CR could be a protective factor for cognitive performance and cognitive decline, and it is more sensitive and inclusive than an individual CR indicator alone.

Depressive Symptoms, Antidepressants, and Clinical Outcomes in Chronic Kidney Disease: Findings from the CRIC Study.

Rationale & Objective: The extent to which depression affects the progression of chronic kidney disease (CKD) and leads to adverse clinical outcomes remains inadequately understood. We examined the association of depressive symptoms (DS) and antidepressant medication use on clinical outcomes in 4,839 adults with nondialysis CKD. Study Design: Observational cohort study. Setting and Participants: Adults with mild to moderate CKD who participated in the multicenter Chronic Renal Insufficiency Cohort Study (CRIC). Exposure: The Beck Depression Inventory (BDI) was used to quantify DS. Antidepressant use was identified from medication bottles and prescription lists. Individual effects of DS and antidepressants were examined along with categorization as follows: (1) BDI <11 and no antidepressant use, (2) BDI <11 with antidepressant use, (3) BDI ≥11 and no antidepressant use, and (4) BDI ≥11 with antidepressant use. Outcomes: CKD progression, incident cardiovascular disease composite, all-cause hospitalizations, and mortality. Analytic Approach: Cox regression models were fitted for outcomes of CKD progression, incident cardiovascular disease, and all-cause mortality, whereas hospitalizations used Poisson regression. Results: At baseline, 27.3% of participants had elevated DS, and 19.7% used antidepressants. Elevated DS at baseline were associated with significantly greater risk for an incident cardiovascular disease event, hospitalization, and all-cause mortality, but not CKD progression, adjusted for antidepressants. Antidepressant use was associated with higher risk for all-cause mortality and hospitalizations, after adjusting for DS. Compared to participants without elevated DS and not using antidepressants, the remaining groups (BDI <11 with antidepressants; BDI ≥11 and no antidepressants; BDI ≥11 with antidepressants) showed higher risks of hospitalization and all-cause mortality. Limitations: Inability to infer causality among depressive symptoms, antidepressants, and outcomes. Additionally, the absence of nonpharmacological data, and required exploration of generalizability and alternative analytical approaches. Conclusions: Elevated DS increased adverse outcome risk in nondialysis CKD, unattenuated by antidepressants. Additionally, investigation into the utilization and counterproductivity of antidepressants in this population is warranted.

We analyzed data from 4,839 nondialysis chronic kidney disease (CKD) patients in the Chronic Renal Insufficiency Cohort Study to explore how depression and antidepressants affect CKD-related outcomes. Using the Beck Depression Inventory (BDI), we assessed depressive symptoms (DS) and identified antidepressant use through medication records. Outcomes included CKD progression, cardiovascular events, hospitalizations, and mortality. Elevated DS at baseline raised the risk of cardiovascular events, hospitalizations, and mortality, regardless of antidepressant use. Antidepressant use alone was associated with higher mortality and hospitalization risks. In comparison to those without elevated DS and no antidepressant use, all other groups faced increased hospitalization and mortality risks. Elevated DS posed a significant risk to nondialysis CKD patients, and antidepressants did not mitigate this risk.

INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC): An NIA and VA-sponsored initiative to increase veteran participation in aging and dementia research.

INTRODUCTION: Older military veterans often present with unique and complex risk factors for Alzheimer's disease (AD) and related dementias. Increasing veteran participation in research studies offers one avenue to advance the field and improve health outcomes. METHODS: To this end, the National Institute on Aging (NIA) and Department of Veterans Affairs (VA) partnered to build infrastructure, improve collaboration, and intensify targeted recruitment of veterans. This initiative, INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC), provided funding for five sites and cross-site organizing structure. Diverse and innovative recruitment strategies were used. RESULTS: Across five sites, 172 veterans entered registries, and 99 were enrolled into ADRC studies. Of the enrolled, 39 were veterans from historically underrepresented racial and ethnic groups. CONCLUSIONS: This initiative laid the groundwork to establish sustainable relationships between the VA and ADRCs. The partnership between both federal agencies demonstrates how mutual interests can accelerate progress. In turn, efforts can help our aging veterans.

Genetic and Clinical Correlates of AI-Based Brain Aging Patterns in Cognitively Unimpaired Individuals.

Importance: Brain aging elicits complex neuroanatomical changes influenced by multiple age-related pathologies. Understanding the heterogeneity of structural brain changes in aging may provide insights into preclinical stages of neurodegenerative diseases. Objective: To derive subgroups with common patterns of variation in participants without diagnosed cognitive impairment (WODCI) in a data-driven manner and relate them to genetics, biomedical measures, and cognitive decline trajectories. Design, Setting, and Participants: Data acquisition for this cohort study was performed from 1999 to 2020. Data consolidation and harmonization were conducted from July 2017 to July 2021. Age-specific subgroups of structural brain measures were modeled in 4 decade-long intervals spanning ages 45 to 85 years using a deep learning, semisupervised clustering method leveraging generative adversarial networks. Data were analyzed from July 2021 to February 2023 and were drawn from the Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) international consortium. Individuals WODCI at baseline spanning ages 45 to 85 years were included, with greater than 50 000 data time points. Exposures: Individuals WODCI at baseline scan. Main Outcomes and Measures: Three subgroups, consistent across decades, were identified within the WODCI population. Associations with genetics, cardiovascular risk factors (CVRFs), amyloid ß (Aß), and future cognitive decline were assessed. Results: In a sample of 27 402 individuals (mean [SD] age, 63.0 [8.3] years; 15 146 female [55%]) WODCI, 3 subgroups were identified in contrast with the reference group: a typical aging subgroup, A1, with a specific pattern of modest atrophy and white matter hyperintensity (WMH) load, and 2 accelerated aging subgroups, A2 and A3, with characteristics that were more distinct at age 65 years and older. A2 was associated with hypertension, WMH, and vascular disease-related genetic variants and was enriched for Aß positivity (ages ≥65 years) and apolipoprotein E (APOE) ε4 carriers. A3 showed severe, widespread atrophy, moderate presence of CVRFs, and greater cognitive decline. Genetic variants associated with A1 were protective for WMH (rs7209235: mean [SD] B = -0.07 [0.01]; P value = 2.31 × 10-9) and Alzheimer disease (rs72932727: mean [SD] B = 0.1 [0.02]; P value = 6.49 × 10-9), whereas the converse was observed for A2 (rs7209235: mean [SD] B = 0.1 [0.01]; P value = 1.73 × 10-15 and rs72932727: mean [SD] B = -0.09 [0.02]; P value = 4.05 × 10-7, respectively); variants in A3 were associated with regional atrophy (rs167684: mean [SD] B = 0.08 [0.01]; P value = 7.22 × 10-12) and white matter integrity measures (rs1636250: mean [SD] B = 0.06 [0.01]; P value = 4.90 × 10-7). Conclusions and Relevance: The 3 subgroups showed distinct associations with CVRFs, genetics, and subsequent cognitive decline. These subgroups likely reflect multiple underlying neuropathologic processes and affect susceptibility to Alzheimer disease, paving pathways toward patient stratification at early asymptomatic stages and promoting precision medicine in clinical trials and health care.