Citations

Abstract Mobility and cognition impairments are common in older adults, but neurodegenerative pathology contributions are unclear. We examined cross-temporal associations of Alzheimer’s Disease (AD)-specific and nonspecific neurodegenerative plasma biomarkers neurofilament light (NfL) with incident mobility and cognitive impairment in the Atherosclerosis Risk in Communities (ARIC) study. We hypothesized NfL would show stronger associations with mobility impairment than p-tau181 in a subset of 1,227 cognitively normal participants with biomarker data and no mobility impairment (mean age=75.5±5.0, 56% female, 23% Black) at visit 5 (2011-13). Participants were classified into five functional groups using data from up to four exams: no impairment (n = 587; referent), mobility impairment only (n = 266; gait speed< 0.8m/s), cognitive impairment only (n = 69; adjudicated dementia), dual impairment (n = 243; both) or decline-free death (n = 262) over a mean 6.3 years (0-11 years) of follow-up. A multinomial regression model estimated association of functional groups with p-tau-181 and NfL jointly, adjusted for cardiovascular and demographic factors, BMI, and kidney function. Relative prevalence ratios (RPR; 95% CI) are presented per one-unit higher log-base-2 transformed biomarker (doubling). For mobility and cognitive functional outcomes, p-tau-181 was more robustly supported [Mobility: RPR=1.36, (1.04,1.77); Cognitive: RPR=1.73, (1.10,2.70); Dual: RPR=1.78, (1.15,2.77)] than NfL [Mobility: RPR=1.14, (0.85,1.53); Cognitive: RPR=1.20, (0.70,2.05); Dual: RPR=1.65, (0.86,3.16)]; higher pTau-181 [RPR=1.60, (1.23,2.09)] and higher NfL [RPR=1.94, (1.39,2.71)] were associated with higher risk of decline-free death. A p-tau-181-x-NfL interaction term was not supported. Findings did not support NfL associations with functional outcomes with consideration of p-tau-181. AD blood biomarkers may help identify individuals at greater risk for multifaceted disability.

Abstract Inpatient boarding (holding patients in the emergency department [ED] while awaiting an inpatient bed) is associated with increased risk of delirium, medication safety events, and hospital mortality in older adults. We investigated boarding trends across age strata to determine if older patients had elevated rates compared to younger patients. Administrative data for ED encounters resulting in admission from 3 healthcare systems (2 Midwest, 1 Northeast) from 1/1/19 to 12/31/24 were reviewed. Age was categorized by strata: < 21, 21-64, 65-74, 75-84, and ≥ 85. Based on the CMS Age Friendly Hospital Measures, the proportion of patients boarding for 3+ hours was calculated within each year and age strata. Boarding rates varied substantially by system and age group. At Systems 1 (S1) and 3 (S3), ≥ 85 patients had the highest rates (S1: 54.9%, S3: 70.9% in 2024) and, at System 2 (S2), all adult patients (21+) had similar rates (20.5-22.4% in 2024). Boarding rates increased in all systems over the study period. At S1 and S3, < 21 patients had the highest average yearly increase in boarding (S1: 7.4%, S3: 3.9%). At S2, boarding increased most in ≥ 85 (23.9%). In this multisystem evaluation, approximately one in two older adults experience ED boarding, with the oldest patients (≥ 85) facing the greatest exposure to boarding in recent years. These findings taken alongside known delays and safety risks associated with boarding and patient care complexity amongst the oldest adults may result in disproportionate harm to some of the most vulnerable patients.

Abstract Although slower gait speed is associated with cognitive impairment, endurance may be more predictive in older adults with faster gait speed. We examined moderating effects of endurance on the relationship of gait speed with incident mild cognitive impairment (MCI) or dementia in cognitively normal ARIC participants (n = 2242, mean age=78.6 + 4.3, 58% female, 19% Black). At the sixth exam, endurance was assessed as distance walked at a fast pace (Two Minute Walk, 2MW); usual 4-meter gait speed was also assessed. Cognitive status was adjudicated during the 6th-9th exams (mean follow-up 5.1 years). Multinomial logistic regression models with a 2MW-x-gait speed interaction term estimated relative risk ratios (RRR) of MCI and dementia relative to normal cognition per SD higher gait speed or 2MW distance, adjusting for demographic and cardiovascular factors. Results used representative continuous gait speed and continuous 2MW distance values. Longer 2MW distance was associated with lower risk of MCI and dementia at gait speed <1m/s [e.g. gait speed=0.8: MCI RRR=0.59, 95%CI(0.42, 0.83); dementia RRR=0.29, (0.13, 0.63)] and with dementia at gait speed>1m/s [gait speed=1.2: RRR=0.28, (0.09, 0.81)], but not with MCI (RRR=0.85, (0.57, 1.26)]. Conversely, faster gait speed was associated with lower risk of MCI at low 2MW [100 m; RRR=0.84, (0.74, 0.94)], but was attenuated at high 2MW (150 m; RRR=0.91, (0.84, 1.00)]. A 2MW-x-gait speed interaction term was supported (p = 0.04), primarily driven by differential MCI associations. Combining endurance and gait speed may be especially helpful in identifying cognitively normal older adults at risk for impending early-stage cognitive impairment.

Abstract Faster gait speed and better endurance have been cross-sectionally and jointly associated with a lower likelihood of dementia. However, gait speed associations plateau above 1m/s, suggesting gait speed may be less predictive at near normal speeds. This study examined prospective associations of gait speed, endurance, and moderating effects of endurance on gait speed associations with incident dementia among ARIC participants without dementia at Visit 6 (2016-2017) who completed assessments of endurance ( 2- Minute Walk (2MW), meters) and usual-pace 4-meter gait speed (m/s) (n = 2767, mean age 78+/- 4.3 years, 43% male, 18% Black). Dementia was adjudicated using neuropsychological tests, functional assessments, informant interviews, and medical/vital record surveillance over a median of 3.3 years follow-up. Cox regression models estimated the hazard ratio (HR, 95% CI) for dementia, incorporating gait speed, 2MW, gait speed-by-2MW interaction, demographic, and cardiovascular factors. In separate models, each standard deviation higher 2MW [HR = 0.62, (0.50,0.76)] and faster gait speed [HR = 0.63, (0.50,0.81)] were associated with lower incident dementia risk. However, when jointly adjusting for 2MW and gait speed, higher 2MW was associated with a 32% lower incident dementia risk [HR = 0.68,(0.51, 0.90)], but faster gait speed was not statistically associated with incident dementia [HR = 0.85, (0.62,1.16)]. Moderating effects were not supported (gait speed-x-2MW interaction, p = 0.14). Although both endurance and gait speed predict dementia, endurance may be more informative across the gait speed spectrum, whereas gait speed may be more feasible for clinical settings. Longer follow-up and more dementia events may better inform differential utilities of gait speed and endurance measures.

Abstract Impaired kidney function is a risk factor for cognitive decline and dementia, but most studies use serum creatinine-based equations to estimate kidney function as estimated glomerular filtration rate (eGFR); these equations include age, also a strong driver of cognitive impairment, and produce eGFR estimates with substantial error compared to gold-standard objective measures of GFR (mGFR). The purpose of this study was to determine eGFR and mGFR associations with cognitive function in African American adults, a population disproportionately impacted by both chronic kidney disease and dementia. We conducted a cross-temporal analysis of 368 participants (Age: 66.4 ± 7.4y, 75% Female) in the Genetic Epidemiology Network of Arteriopathy study with eGFR (CKD-EPI 2021 Creatinine Race-Free Equation) and mGFR assessed. eGFR was assessed using the CKD-EPI 2021 Creatinine Race-Free Equation and mGFR (urinary clearance of non-radiolabeled iothalamate). Memory (Rey Auditory Verbal Learning Test; RAVLT) and executive function (Digit Symbol Substitution Test; DSST) were assessed. Linear regression models were used to relate eGFR, mGFR, and serum creatinine to cognitive function with and without adjustment for age and sex. In unadjusted models, eGFR was positively associated with DSST scores (β = 0.19, 95%CI:0.11, 0.27) and RAVLT scores (β = 0.10, 95%CI:0.04, 0.16). mGFR was marginally associated with DSST scores (β = 0.07, 95%CI:-0.00, 0.14), but not RAVLT scores (β = 0.03, 95%CI:-0.01, 0.07). Associations of serum creatinine with cognitive function were mostly null to marginal. Age and sex adjustment greatly attenuated all associations. The observed differential renal function associations with cognition suggest age may largely explain prior reported associations.

Abstract Multiple lines of evidence suggest that calorie restriction may slow biological processes related to aging and extend lifespan. To determine whether calorie restriction affects mitochondrial function, we treated fibroblasts from adult donors with serum samples obtained from participants of the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study. The CALERIE study enrolled healthy, non-obese middle-aged (average 38y.o) participants to examine the effects of long-term calorie restriction. We studied the serum samples of 177 participants (calorie restriction CR = 121, ad libitum AL = 56) who had specimens available at two timepoints (12 and 24 months). We assessed the basal and maximal mitochondrial respiration of fibroblasts treated with dilute serum for 24 hours. Our results show that the baseline basal and maximal mitochondrial respiration of fibroblasts is positively correlated with the adiposity of the serum donor (R = 0.112, P = 0.137; R = 0.183, P = 0.015, respectively). Interestingly, treatment of fibroblasts with serum collected after 12 months of calorie restriction causes a decrease in both basal and maximal mitochondrial respiration (P = 0.1854; P = 0.0623, respectively). Fibroblasts treated with serum collected after 24 months of calorie restriction exhibited a further reduction in both basal and maximal mitochondrial respiration (P = 0.0174; P = 0.0092, respectively). These findings suggest that the serum of individuals on long term calorie restriction diet comprises factors that can reduce oxidative phosphorylation. This reduction in bioenergetic capacity may align with the theory that calorie restriction leads to a cellular energy-conserving state, which could have implications for cellular aging and metabolism.

Abstract Lower cerebral perfusion is associated with adverse outcomes, but risk factors are poorly understood. This study examined associations of cumulative systolic blood pressure [SBP], diabetes, and BMI from mid- to late-life with late-life cerebral perfusion, using whole-brain MRI Arterial Spin Labeling (ASL). Cumulative exposures were defined as either average continuous SBP or BMI across visits or number of years with diabetes, hypertension, or obesity. Multiple regression, adjusted for age and gender, estimated ASL (β: 95% CI) among participants without prevalent conditions at baseline in participants with ASL data from the Atherosclerosis Risk in Communities Study (ARIC; Jackson, MS; n = 100; age=81±3 years; 65% Female; 100% Black participants; 34 years retrospective risk factor assessments (1987-2021); pulsed ASL, 8/2021-1/2024) and the Mayo Clinic Study of Aging (MCSA; Rochester, MN; n = 537; age=71±13 years; 36.3% Female, 100% White participants; 18 years retrospective risk factor assessments (2005-2023); pseudo-continuous ASL 2/2023-3/2024). A 10 mmHg higher cumulative SBP was associated with a 0.04 lower ASL (MCSA β=-0.04; -0.01, -0.07; ARIC β=-0.04; -0.09, 0.01). A 10 kg/m2 higher cumulative BMI was associated with a 0.30 lower ASL (-0.51, -0.08) in ARIC and 0.03 lower ASL (-0.16, 0.10) in MCSA participants. Every five additional years of diabetes exposure was associated with a 0.03 (-0.06, -0.01) lower ASL in ARIC and 0.11 (-0.27, 0.05) lower ASL in MCSA participants. High BP, obesity, and diabetes may contribute to poor cerebral perfusion over extended exposures from midlife. Longer risk factor assessment periods and different ASL techniques may explain differences in the cohorts.

Abstract Extensive studies in rodents have shown that senescent cells accumulate across tissues and their clearance leads to improvements in healthspan and lifespan. Based on these studies, there is intense interest in translating these findings into humans. Based on ClinicalTrials.gov, there are currently 26 ongoing studies on “senolytics” and 32 on “fisetin”. However, to date, there are only 9 published clinical trials of senolytics, only 2 of which included a control group. Collectively, the initial findings from these trials have indicated possible biological efficacy of senolytics (dasatinib + quercitin) in improving biomarkers of healthspan in humans with no significant safety concerns. However, these initial studies also highlight the potential heterogeneity of aging mechanisms in humans and argue for a more personalized approach in future senolytic trials. Specifically, it is likely going to be critical to identify aging individuals with a sufficiently high burden of senescent cells that would result in a beneficial effect from the senolytic intervention.

Abstract As a group, family caregivers of people with dementia (PWDs) have substantially elevated levels of depression and anxiety, compared to same-aged non-caregiving adults. However, there is striking variation in mental health among individual caregivers. Previous research on predictors of the sources of these individual differences has focused on characteristics of individual caregivers and PWDs (rather than on the caregiver-PWD relationship), self-report measures (rather than behavioral measures), and negative emotion (rather than positive emotion). We examined 185 caregiver-PWD dyads who had an unrehearsed 10-minute conversation about an area of conflict in the laboratory. Video recordings were coded for Behavioral Indicators of Positivity Resonance (BIPR), which derives from Positivity Resonance Theory and assesses dyad-level behavioral expressions of positive affect, mutual warmth, and synchrony. Caregivers reported their level of depression, anxiety, and emotional well-being and PWDs underwent a comprehensive neurological and neuropsychological evaluation. Pearson’s correlations revealed that greater dyad-level BIPR was associated with caregivers’ higher emotional well-being (r(181) = .19, p = .008), lower depression (r(179) = -.17, p = .025), and lower anxiety (r(180) = -.15, p = .045). Regression analyses revealed that these associations were still obtained after controlling for caregiver age and sex and PWD dementia severity, cognitive impairment, and neuropsychiatric behavior (emotional well-being ß = .18, p = .012; depression ß = -.15, p = .039; anxiety ß = -.15, p = .044). Future studies should determine whether interventions that increase co-experienced positive emotions among caregiver-PWD dyads help buffer caregivers from adverse mental health consequences.

Abstract Blood-based biomarkers show promise as a noninvasive method for measuring Alzheimer’s disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late-life brain morphology in community-dwelling populations requires further investigation. Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received underwent 3 Tesla magnetic resonance imaging scans. Whole-brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993-95, mean age 59.0 years) and late-life (2011-13, mean age 76.8 years) from a subsample of 1,515 participants (60.7% female, 25.5% Black adults) were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid-β (Aβ)42/40, phosphorylated tau at threonine 181 (p-Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of blood-based biomarkers from midlife, late-life, and the change from midlife to late-life with cortical thickness in late-life. In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p-Tau181 and increases from midlife to late-life in NfL and GFAP were associated with lower cortical thickness in late-life. Concurrent measures of p-Tau181, NfL, and GFAP were associated with lower cortical thickness in late-life and exhibited a stronger association among participants ≥75 years old compared to participants <75 years old. Additional longitudinal research is needed to determine whether blood-based biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.