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Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

Introduction: Plasma biomarkers of Alzheimer’s disease (AD), including amyloid-β (Aβ42/Aβ40), phosphorylated tau (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) have shown strong reliability in predicting dementia risk. White matter hyperintensities (WMH) represent a major vascular contributor to dementia. We investigated how plasma biomarkers of AD interact with WMH on MRI to influence incident dementia risk. Methods: We included dementia-free participants from the Atherosclerosis Risk in Communities (ARIC) Study who underwent MRI and plasma biomarker assessment at Visit 5 (2011–2013). WMH was quantified and considered continuously (log-transformed and standardized), and in tertiles. Plasma biomarkers were log-base-2-transformed. Cox proportional hazards models were used to estimate dementia risk over 10 years associated with plasma biomarkers and WMH, independently and multiplicatively. Models were adjusted for demographic variables (age, sex, race, and education), vascular risk factors (hypertension, diabetes, smoking status, body mass index, and estimated glomerular filtration rate), and APOE ε4 status. Results: Among 1,538 participants (aged 67- 90 years, 29% Black), 30% ( N = 462) developed dementia over the 10-year follow-up period. For every doubling of plasma Aβ42/Aβ40 , indicating lower amyloid burden, dementia risk decreased, while doubling of p-tau 181 , NfL, and GFAP were each associated with increased dementia risk, in separate models; each of these associations was independent of WMH (Table 1). Additionally, dementia risk increased per SD increase in WMH, independent of each plasma biomarker. Although no multiplicative interaction terms reached statistical significance (p<0.05), there was suggestive evidence that Aβ42/Aβ40 and GFAP have smaller effect sizes on dementia risk in subgroups at the highest WMH tertile (p-interactions<0.10; see Table 2). Discussion: Plasma biomarkers and WMH independently predict dementia risk over 10 years, though there remained limited evidence of multiplicative effects. Plasma biomarkers may be less important for dementia risk in individuals who also have extensive WMH. These findings emphasize the importance of incorporating both AD-specific plasma markers as well as indicators of cerebral small vessel disease, such as WMH, into dementia risk profiling.

Abstract Background Decreased kidney function, indicated by a lower estimated glomerular filtration rate (eGFR), may affect interpretation of Alzheimer's disease (AD) blood biomarkers, including phosphorylated tau ( p ‐tau) and amyloid‐beta (Aβ) peptides, due to altered clearance. However, there is limited data available to determine the influence of eGFR on these biomarkers and whether it differs by biomarker or assay type, especially in racially diverse studies of community‐based older adults. Methods We used data from 557 participants in the Mayo Clinic Study of Aging (Rochester, MN n = 182; age 79±8 years; 36.3% Female, White participants) and the UMMC MIND Center‐Mayo Clinic Study of Aging (Jackson, MS n = 375; age 69±8 years; 73% Female 27% Black participants). eGFR was determined using the 2021 CKD‐EPI Creatinine equation. Plasma biomarkers were measured using the Lumipulse immunoassays for p ‐tau217, Aβ42, and Aβ40 (Fujirebio Diagnostics; n = 420); or the mass spectrometry‐based PrecivityAD2 assay (C2N Diagnostics; n = 253) for p ‐tau217, np‐tau217, Aβ42, and Aβ40. Common ratio values were calculated. Aβ42/40 measures were inverted so higher values are worse for all biomarkers. Log base‐2 transformed regression analysis related eGFR to each single analyte and ratio; coefficients (95% CI) reflect estimated doubling in biomarker per doubling in eGFR. Group specific [MN White ( n = 182), MS White ( n = 224), MS Black ( n = 151) participants] estimates are reported, as the distribution of social determinants of health can vary across populations and locations. Results Lower eGFR was associated with higher (worse) AD‐plasma biomarkers, and group stratified estimates were mostly consistent (Figure 1). Ratios of biomarkers diminished but did not entirely alleviate associations with eGFR. For example, MN White participants’ C2N p ‐tau217 association of ‐1.47 (‐1.94, ‐1.00), was attenuated to ‐0.67 (‐1.11, ‐0.22), when using p ‐tau217/np‐tau217. Conclusions Kidney function may be associated with AD‐plasma biomarker values, even with common ratio corrections. There was not strong evidence for highly differential associations of eGFR by race/site categories, though sample sizes are currently limited. The implications for diagnosis and risk classification need to be explored further to support health equity. Optimal consideration of comorbidities on blood biomarker concentrations must continue to be informed by investigation in large, racially and ethnically diverse, community‐based studies.

Abstract Background Plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration provide a non‐invasive method to assess brain pathology associated with dementia and cognitive decline. However, it remains unclear whether these biomarkers are differentially associated with changes in specific cognitive domains or how they relate to subsequent cognitive change in participants with or without cognitive impairment. Methods Plasma biomarkers were assayed in a subset of ARIC participants using Quanterix SiMoA technology on stored specimens collected in midlife (visit 3: 1993‐95, mean age: 59) and late‐life (visit 5: 2011‐13, mean age: 77). Biomarkers included amyloid‐β 42 to amyloid‐β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Factor scores for global cognition and cognitive domains (memory, language, executive function) were calculated from ten neuropsychological tests administered at visits 5 (2011‐13), 6 (2016‐17), 7 (2018‐19), 8 (2020), and 9 (2021‐22). Linear mixed effects models with multiple imputation of pre‐death cognitive change estimated the association between biomarkers in midlife and late‐life, and biomarker change from midlife to late‐life, with 5‐year change in late‐life global and domain‐specific cognition, adjusting for demographics, lifestyle and cardiovascular risk factors, and APOE‐ε4 status. Exploratory analyses examined effect modification of the biomarker‐global cognition associations by visit 5 adjudicated cognitive impairment. Results Among 1515 participants with plasma biomarkers (60.7% female, 25.5% identified as Black), 39% had late‐life cognitive impairment (Table 1). Higher midlife NfL and GFAP were associated with faster 5‐year declines in global cognition and language during late‐life (Table 2). Only midlife NfL was associated with faster late‐life memory decline. No midlife biomarkers were associated with executive function. In late‐life, lower Aβ42:Aβ40 and higher p ‐Tau 181, NfL, and GFAP were associated with faster declines in global cognition, memory, and language. Midlife to late‐life changes in p ‐Tau 181, NfL, and GFAP were associated with declines in global cognition and language. No consistent effect modification by cognitive impairment was observed (Figure 1). Conclusions Plasma biomarkers of AD pathology, neuronal injury, and astrogliosis, measured at different life epochs (midlife vs. late‐life) show distinct association patterns with subsequent changes in cognitive function across domains.

Abstract Background Plasma 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. Method Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received an adjudicated cognitive diagnosis and 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 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 plasma biomarkers from midlife, late‐life, and the change from midlife to late‐life with cortical thickness in late‐life. Interactions and effect modification by age were examined in exploratory analyses. Result The sample (Table 1) included 920 (60.7%) women, 387 (25.5%) Black participants, 513 (33.9%) participants with mild cognitive impairment, and 85 (5.6%) participants with dementia. The average age in late‐life was 76.8 (5.3 SD) years and the average cortical thickness was 2.27 (0.11 SD) millimeters. Cortical thickness was lower in individuals with adjudicated mild cognitive impairment or dementia compared to individuals without cognitive impairment (2.25 mm versus 2.29 mm, p <0.0001). 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 (Table 2). Concurrent measures of plasma biomarkers in late‐life were associated with lower cortical thickness (Table 2) and exhibited a stronger association among participants ≥75 years compared to <75 years (Table 3). Conclusion Plasma biomarkers of Alzheimer's disease pathology and neurodegeneration obtained in midlife and late‐life were associated with late‐life differences in cortical thickness. Additional longitudinal research is needed to determine whether plasma biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.

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&lt; 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 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 &lt;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&gt;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.