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Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals.

ABSTRACT: Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C₂N Diagnostics' PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.

SUBMITTER: Xiong C

PROVIDER: S-EPMC11219932 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals.

Xiong Chengjie C Luo Jingqin J Wolk David A DA Shaw Leslie M LM Roberson Erik D ED Murchison Charles F CF Henson Rachel L RL Benzinger Tammie L S TLS Bui Quoc Q Agboola Folasade F Grant Elizabeth E Gremminger Emily N EN Moulder Krista L KL Geldmacher David S DS Clay Olivio J OJ Babulal Ganesh G Cruchaga Carlos C Holtzman David M DM Bateman Randall J RJ Morris John C JC Schindler Suzanne E SE

Nature communications 20240702 1

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C<sub>2</sub>N Diagnostics' PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individu ...[more]

PMID: 38956096

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Project description:IntroductionIt is critical to develop more inclusive Alzheimer's disease (AD) research protocols to ensure that historically excluded groups are included in preclinical research and have access to timely diagnosis and treatment. If validated in racialized groups, plasma AD biomarkers and measures of subtle cognitive dysfunction could provide avenues to expand diversity in preclinical AD research. We sought to evaluate the utility of two easily obtained, low-burden disease markers, plasma amyloid beta (Aβ)42/40, and intra-individual cognitive variability (IICV), to predict concurrent and longitudinal cognitive performance in a sample of Black adults.MethodsTwo hundred fifty-seven Black participants enrolled in the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) study underwent at least one cognitive assessment visit; a subset of n = 235 had plasma samples. Baseline IICV was calculated as the standard deviation across participants' z scores on five cognitive measures: Rey Auditory Verbal Learning Test Delayed Recall, Trail Making Test Parts A and B (Trails A and B), and Boston Naming Test. Using mixed effects regression models, we compared concurrent and longitudinal models to baseline plasma Aβ42/40 or IICV by age interactions. PrecivityAD assays quantified baseline plasma Aβ42/40.ResultsIICV was associated with concurrent/baseline performance on several outcomes but did not modify associations between age and cognitive decline. In contrast, plasma Aβ42/40 was unrelated to baseline cognitive performance, but a pattern emerged in interactions with age in longitudinal models of Trails A and B and Rey Auditory Verbal Learning Test total learning trials. Although not significant after correcting for multiple comparisons, low Aβ42/40 was associated with faster cognitive declines over time.DiscussionOur results are promising as they extend existing findings to an Black American sample using low-cost, low-burden methods that can be implemented outside of a research center, thus supporting efforts for inclusive AD biomarker research.

Project description:ImportanceCOVID-19 has disproportionately affected Black individuals in the US; however, vaccination rates among Black individuals trail those among other racial groups. This disparity is often attributed to a high level of vaccine hesitancy among Black individuals, but few studies have examined changes in vaccine hesitancy over time.ObjectivesTo compare changes in vaccine hesitancy between Black and White individuals in the US and to examine mechanisms that might help explain the observed differences.Design, setting, and participantsThis survey study used 7 waves of data collected using a panel design. A total of 1200 English-speaking adults in the US were recruited from a nonprobability online panel to construct a census-matched sample. Participants were contacted monthly between December 9, 2020, and June 16, 2021.Main outcomes and measuresThe main outcome of interest was self-reported vaccination intention, measured on a 6-point scale (where 1 indicates extremely unlikely and 6 indicates extremely likely). Beliefs about the safety, effectiveness, and necessity of COVID-19 vaccines were measured on a 5-point Likert scale, with higher scores denoting greater agreement.ResultsThe baseline data included 1200 participants (693 women [52.0%; weighted]; 921 White individuals [64.0%; weighted], 107 Black individuals [12.2%; weighted]; weighted mean [SD] age, 49.5 [17.6] years). The survey participation rate was 57.0% (1264 of 2218). Black and White individuals had comparable vaccination intentions in December 2020, but Black individuals experienced larger increases in vaccination intention than White individuals relative to baseline in March 2021 (b = 0.666; P < .001), April 2021 (b = 0.890; P < .001), May 2021 (b = 0.695; P < .001), and June 2021 (b = 0.709; P < .001). The belief that the vaccines are necessary for protection also increased more among Black than White individuals in March 2021 (b = 0.221; P = .01) and April 2021 (b = 0.187; P = .04). Beliefs that the vaccines are safe and effective (b = 0.125; P < .001) and necessary (b = 0.405; P < .001) were positively associated with vaccination intention. There was no evidence that these associations varied by race.Conclusions and relevanceThis survey study suggests that the intention of Black individuals to be vaccinated was initially comparable to that of White individuals but increased more rapidly. There is some evidence that this increase is associated with changes in beliefs about the vaccine. Vaccination rates continue to be lower among Black individuals than White individuals, but these results suggest that this might be less likely the result of vaccine hesitancy than other factors.

Project description:BackgroundCathepsin D (CatD) is a lysosomal protease that degrades both the amyloid β-protein (Aβ) and the microtubule-associated protein, tau, and has been genetically linked to late-onset Alzheimer disease (AD). Here, we sought to examine the consequences of genetic deletion of CatD on Aβ proteostasis in vivo and to more completely characterize the degradation of Aβ42 and Aβ40 by CatD.MethodsWe quantified Aβ degradation rates and levels of endogenous Aβ42 and Aβ40 in the brains of CatD-null (CatD-KO), heterozygous null (CatD-HET), and wild-type (WT) control mice. CatD-KO mice die by ~ 4 weeks of age, so tissues from younger mice, as well as embryonic neuronal cultures, were investigated. Enzymological assays and surface plasmon resonance were employed to quantify the kinetic parameters (KM, kcat) of CatD-mediated degradation of monomeric human Aβ42 vs. Aβ40, and the degradation of aggregated Aβ42 species was also characterized. Competitive inhibition assays were used to interrogate the relative inhibition of full-length human and mouse Aβ42 and Aβ40, as well as corresponding p3 fragments.ResultsGenetic deletion of CatD resulted in 3- to 4-fold increases in insoluble, endogenous cerebral Aβ42 and Aβ40, exceeding the increases produced by deletion of an insulin-degrading enzyme, neprilysin or both, together with readily detectable intralysosomal deposits of endogenous Aβ42-all by 3 weeks of age. Quite significantly, CatD-KO mice exhibited ~ 30% increases in Aβ42/40 ratios, comparable to those induced by presenilin mutations. Mechanistically, the perturbed Aβ42/40 ratios were attributable to pronounced differences in the kinetics of degradation of Aβ42 vis-à-vis Aβ40. Specifically, Aβ42 shows a low-nanomolar affinity for CatD, along with an exceptionally slow turnover rate that, together, renders Aβ42 a highly potent competitive inhibitor of CatD. Notably, the marked differences in the processing of Aβ42 vs. Aβ40 also extend to p3 fragments ending at positions 42 vs. 40.ConclusionsOur findings identify CatD as the principal intracellular Aβ-degrading protease identified to date, one that regulates Aβ42/40 ratios via differential degradation of Aβ42 vs. Aβ40. The finding that Aβ42 is a potent competitive inhibitor of CatD suggests a possible mechanistic link between elevations in Aβ42 and downstream pathological sequelae in AD.

Dataset Information

Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals.

Publications

Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals.

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