Blackshear, Chad

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 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 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.

AbstractBackgroundOlder adults with dual cognitive and mobility impairments have higher financial costs and poorer quality of life than adults with either impairment alone. Blood biomarkers of Alzheimer Disease (AD) pathology (Aβ42, Aβ40 and p‐tau181) and neurodegeneration (neurofilament light (NFL) and glial fibrillary acidic protein (GFAP)) may identify individuals at risk for both mobility and cognitive impairment and provide novel insights into mechanistic underpinnings.MethodBlood biomarkers (SiMoA Quanterix N4PE, p‐tau181 single‐plex) were available in a subsample of 1751 ARIC study participants at Visit 5 (V5, 2011‐13, mean age 76.2 years (5.3), 41% men, 28% Black); Aβ42 was reversed and adjusted for Aβ40 (‐Aβ42|40) for consistent directions of associations (higher=worse). Usual gait speed and cognitive status were assessed over 8 years at V5, V6 (2016‐17), and V7 (2017‐18). Participants were categorized by V5 impairment: mobility‐only (gait speed <0.8m/s, n=430), cognitive‐only (expert‐adjudicated dementia, n=38), dual (n=54), or neither (referent, n=1229). Multinomial regression models examined relative risk ratios (RRR) of V5 log‐transformed biomarkers with prevalent impairments and, among those with neither impairment at V5, incident impairments through V7. All models adjusted for V5 age, sex, self‐reported race (Black or White), renal function, and body mass index.ResultHigher levels of all biomarkers were associated with greater risk of prevalent impairment in mobility, cognitive, or dual domains (Figure A). Over 8‐years of follow‐up, incident impairments included 471 participants with only mobility impairments, 39 with only cognitive impairments, 55 with dual impairments, and 168 died without developing any impairment. All biomarkers were associated with incident dual impairment per IQR higher biomarker: p‐tau181 (RRR=2.54; 95% CI: 1.45, 4.44), ‐Aβ42|40 (RRR=1.66; 1.31, 2.09), NfL (RRR=2.69; 1.22, 5.91) and GFAP (RRR=2.13; 1.07, 4.25). P‐tau181, ‐Aβ42|40, and GFAP were also associated with incident cognitive‐only impairment, while P‐tau181, NFL and GFAP were associated with incident mobility‐only impairment. (Figure B).ConclusionBlood biomarkers of brain health may be useful tools for earlier identification of those at risk for cognitive, mobility, or dual declines, facilitating earlier targeted interventions. Potential differences in AD‐pathology versus neurodegeneration blood biomarker relationships with outcomes of mobility and cognition may help to identify more targeted interventions for both.

Abstract Background Relationships of midlife inflammation with late‐life mobility and influences of chronic health conditions, race, and social determinants of health (SDoH) on these relationships are poorly understood. Methods Among 4758 community‐dwelling participants (41% men, 20% Black), high‐sensitivity C‐reactive protein (hsCRP) was measured over 20+ years: in midlife at study visit 2 (V2: 1990–1992, 47–68 years); at V4 (1996–1998, 53–74 years); and with concurrent late‐life 4‐m gait speed at V5 (2011–2013, 67‐88 years, mean 75 years). SDoH measures included race, the national‐rank area deprivation index, education, and income. We examined associations of late‐life gait speed with midlife hsCRP (V2 continuous and clinically high ≥3 mg/L), with 20‐year hsCRP history from midlife (V2–V5 average continuous hsCRP and clinically high ≥3 mg/L) and with inflammation accumulation (visits and years with high hsCRP). Regression models adjusted for demographic, cardiovascular, and SDoH measures; effect modification by the presence of other common chronic conditions (obesity, diabetes, hypertension) and race were examined, with and without accounting for SDoH. Results High midlife hsCRP was associated with slower late‐life gait speed, even among those without chronic conditions in midlife: −4.6 cm/s (95% CI: −6.4, −2.8). Importantly, sustained high hsCRP was associated with a 20‐year slowing of −10.0 cm/s (−14.9, −5.1) among those who never experienced obesity, diabetes, or hypertension over the 20‐year period. Associations were similar between Black participants, −3.8 cm/s (−6.9, −0.7) and White participants −3.3 (−4.5, −2.2) per interquartile range of midlife hsCRP; effect modifications by chronic conditions and race were unsupported throughout. Results were robust to accounting for SDoH or otherwise; however, worse SDoH was associated with higher inflammation and slower gait speed in both Black and White participants. Conclusions Inflammation in midlife may contribute to clinically meaningful late‐life slowing of gait speed, even among otherwise healthy‐appearing adults and regardless of race and socioeconomic disadvantage. Regular monitoring and interventions for inflammation may be warranted from midlife.

Abstract Brain imaging-based biomarkers of neuropathology are associated with mobility in older adults, but the relation of regional microstructural integrity to gait speed in the context of a broader neuropathological profile is less understood. We examined cross-sectional associations of microstructural integrity with 4-meter usual-pace gait speed (cm/s) in a subsample of ARIC study participants who completed 3T MRI brain scans with diffusion tensor imaging(2011-13; n=1785; mean age=76.2±5.3, 60% Female, 28% Black). We considered total brain and six regional averages of fractional anisotropy (FA; lower=worse microstructural integrity) and mean diffusivity (MD; higher=worse microstructural integrity): frontal, temporal, parietal, occipital, anterior and posterior corpus callosum. Associations were tested in multivariable linear regression models adjusted for demographics, cardiovascular risk factors, and with and without additional neuropathological indices: total brain volume, white matter hyperintensities, infarcts, and microhemorrhages. When modeled separately, all neuropathology indices were associated with slower gait speed. Every standard deviation(SD) higher total brain FA was associated with +2.56 cm/s gait speed (95%CI: 1.64,3.48) and every SD higher MD was associated with -4.27 cm/s gait speed (-5.34,-3.20). All regional estimates were comparable. When adjusted for all other neuropathology indices, only posterior corpus callosum FA (β=1.72; 0.67,2.77), total MD (β=-1.63; -3.02,-0.25), frontal lobe MD (β=-1.76; -3.03,-0.48), and temporal lobe MD (β=-1.40; -2.78,-0.02) remained significantly associated with gait speed. Microstructural integrity is an informative measure of brain pathology in relation to mobility, with regional measures tied to executive, memory, and somatosensory function being more informative when a broader neuropathological profile is considered.

Abstract Plasma-based biomarkers of amyloid beta (Aβ), a neuropathological hallmark of Alzheimer’s disease, show promise in predicting cognitive impairment and mapping onto cerebral amyloidosis, but little is known about how midlife plasma Aβ associates with late-life cognitive outcomes. Midlife plasma variants Aβ42 and Aβ40 were measured using a fluorimetric bead-based immunoassay in a subsample of visit 3 ARIC participants (1993-95; n=2585, mean age=59.4±5.2, 57% female, 23% African American). We investigated the relationship between midlife plasma Aβ and late-life mild cognitive impairment (MCI; n=923) and dementia (n=628) diagnosed from 2011-19. Multinomial logistic regressions estimated relative risk ratios (RRR) of MCI, dementia, and death vs normal cognitive status as a function of:(1) Aβ42:Aβ40 ratio, (2) Aβ42 and Aβ40 included as separate terms, and (3) Protected Aβ group (participants with Aβ42≥46 pg/ml and Aβ40 &lt;233 pg/ml). Adjusters included age, sex, education, site-race, and APOE4. Every doubling of midlife plasma Aβ42:Aβ40 up to a threshold of 0.20 was associated with 41% lower risk of developing MCI/dementia in comparison to cognitively normal (RRR=0.59 [95% CI:0.42, 0.82]), with no association for ratio values ≥0.20. Every standard deviation increase in plasma Aβ42 was associated with 17% lower risk of dementia (RRR=0.83 [0.70, 0.99]), whereas every standard deviation increase in plasma Aβ40 was associated with 16% higher risk of MCI (RRR=1.16 [1.02, 1.31]). The protected midlife plasma Aβ group had 86% lower risk of late-life dementia vs all others (RRR=0.14 [0.04, 0.47]). Early measurement of plasma Aβ may prove an accessible and effective population screener for future cognitive impairment.