Citations

BACKGROUND: White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease but reflect late-stage injury. Diffusion magnetic resonance imaging (MRI) biomarkers have been proposed to capture earlier small vessel disease-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. METHODS: We identified 2077 participants from the population-based cohort study of the Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50–101 years) collected between 05/2005 and 09/2024 with longitudinal neuroimaging. Using multioutput nonlinear mixed-effects models in those with at least 2 fluid-attenuated inversion recovery-MRI and diffusion MRI scans, we characterized the temporal progression of WMH and 4 diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum, peak width of skeletonized mean diffusivity, free water, and Arteriolosclerosis-score, which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). RESULTS: The study population had a mean age of 78 years, 47% were women, 28% were APOE ε4 allele carriers, and 80% were cognitively unimpaired, with an average follow-up of 5.2 years (SD, 4.3 years) for fluid-attenuated inversion recovery-MRI and 4.3 years (SD, 3.9 years) for diffusion MRI. Arteriolosclerosis-score, fractional anisotropy of the genu of the corpus callosum, free water, and peak width of skeletonized mean diffusivity became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH become abnormal (half-width of CI <1 year), respectively. Global markers (Arteriolosclerosis-score, free water, peak width of skeletonized mean diffusivity, and WMH) were correlated, indicating shared substrates of widespread white matter injury. Fractional anisotropy of the genu of the corpus callosum, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Female participants showed earlier WMH, fractional anisotropy of the genu of the corpus callosum, and Arteriolosclerosis-score abnormalities, whereas male participants exhibited earlier peak width of skeletonized mean diffusivity and free water abnormalities. CONCLUSIONS: Diffusion MRI biomarkers were abnormal at least a decade before WMH become abnormal in the population, revealing a prolonged phase of early small vessel disease and highlighting their potential for small vessel disease prevention.

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: Diabetes, a modifiable risk factor for dementia, is thought to impart increased risk of dementia through cerebral small vessel disease. While the importance of diabetes in midlife is well-documented, the influence of different glycemic levels, duration of diabetes, and Alzheimer’s disease genetic risk (apolipoprotein [ APOE ] ε4 genotype) in late-life on dementia risk remains uncertain. This could have implications for individualized prevention strategies. In this study, we investigated whether a higher glycemic level and longer duration of diabetes in late-life is associated with a higher risk of dementia, and whether associations vary by APOE ε4 genotype. Methods: We performed a prospective cohort analysis with the Atherosclerosis Risk in Communities Study using up to 11 years of follow-up (baseline, 2011-2013). We defined diabetes as glycated hemoglobin A1c (HbA 1c ) ≥6.5%, self-reported physician diagnosis, or use of any diabetes medication. Among those with diabetes, we categorized participants as having a lower glycemic level (HbA 1c <7%) or higher level (HbA 1c ≥7%), and duration as short (<5 years) or long (≥5 years). We estimated hazard ratios (HR) for incident dementia by HbA 1c levels and by diabetes duration in separate multivariable-adjusted Cox regression models. We tested for statistical multiplicative interaction on the relative risk of dementia by fitting interaction terms between diabetes measures and APOE ε4 genotype in separate regression models. Results: In 5030 participants without dementia (mean age, 75.4 years; 58.6% female; 21% Black; 28% with diabetes), there were 1167 (23.2%) incident dementia cases over a median follow-up of 9.0 years. Compared to no diabetes, a lower glycemic level and higher level were both associated with elevated dementia risk ( P -trend <.0001; Table). A higher glycemic level was associated with an elevated risk of dementia relative to a lower level (HR=1.47 [95% CI: 1.22-1.77]; Table). Compared to no diabetes, both shorter duration and longer duration were associated with an increase in dementia risk ( P -trend <.0001; Table). Longer duration was associated with an increased risk of dementia relative to shorter duration (HR=1.57 [95% CI: 1.24-1.98]; Table). Associations for glycemic level and diabetes duration did not significantly differ by APOE ε4 genotype (all P >.05). Conclusions: Diabetes management in older adults that includes lower glycemic goals may help reduce dementia risk.

Abstract Background White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease (SVD) but reflect late-stage injury. Diffusion MRI based biomarkers have been proposed to capture earlier SVD-related microstructural damage but their temporal progression relative to WMH and the risk factors associated with this progression have not been explored. Methods We analyzed longitudinal neuroimaging data from 2,047 participants from a population-based cohort study (aged 49-101 years, 47% female). Using multi-output nonlinear mixed-effects models, we characterized the temporal progression of WMH and four diffusion MRI based biomarkers: fractional anisotropy of the genu of the corpus callosum (Genu-FA), peak width of skeletonized mean diffusivity (PSMD), free water (FW), and Arteriolosclerosis-score (ARTS). Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, and cardiometabolic conditions). Results ARTS, Genu-FA, FW, and PSMD became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH, respectively. Global markers (ARTS, FW, PSMD, WMH) were correlated, indicating shared substrates of widespread white matter injury. Genu-FA, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, Genu-FA, and ARTS abnormalities whereas males exhibited earlier PSMD and FW abnormalities. Conclusions Diffusion MRI based biomarkers capture microstructural injury at least a decade before appearance of WMH, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.

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 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.