Burden of cerebral small vessel disease modifies relationship between some plasma Abeta 42/40 assays, but not p‐tau181 assays, with amyloid PET

Abstract

AbstractBackgroundWe aimed to determine if burden of cerebral small vessel disease (CSVD) modifies the relationship of plasma amyloid‐beta (Abeta) 42/40 ratio and/or plasma p‐tau 181 with amyloid PET.MethodWe studied N = 100 participants from the Alzheimer’s Disease Neuroimaging Initiative with 1) Abeta‐42/40 biomarker levels using Quanterix SIMOA (Quanterix), Washington University Mass Spectroscopy (WashU), Simoa HD‐X 4Plex, Roche Elecsys, Shimadzu Mass Spectroscopy, and Gothenburg Mass Spectroscopy, 2) p‐tau181 plasma biomarker levels using Lumipluse G, Roche Elecsys, Simoa p‐tau181V2 Advantage (Simoa Advntage), Simoa p‐tau181, 3) MRI brain, and 4) amyloid‐PET. We stratified by CSVD bruden tertile (calculated from total white matter FLAIR hyperintensity volume). Amyloid positivity was defined as standardized uptake value ratio ≥ 1.11 for florbetapir PET scans. We used box plots to visualize plasma Abeta‐42/40 and p‐tau181 levels stratified by Amyloid‐PET positivity and CSVD tertile. Using logistic regression models, we tested for an interaction between CSVD and plasma Abeta‐42/40 ratio or p‐tau181 on amyloid PET positivity in unadjusted models and models adjusted for age, Clinical Dementia Rating, and presence of ≥1 apolipoprotein E4 allele (ApoE4+).ResultThe cohort had an average age of 77 years, was 56% female, 50% cognitively normal, and 42% ApoE4+ (Table1). We found significant interactions between CSVD and plasma Abeta‐42/40 ratio on amyloid‐PET positivity for Quanterix (raw/adjusted: p = 0.035/p = 0.049), Simoa HD‐Plex (p = 0.047/p = 0.047), and Gothenburg assays (p = 0.026/p = 0.030), with worst discrimination between amyloid‐PET positivity among participants with highest CSVD burden (Figure1A). The Quanterix and Gothenburg assay demonstrated near total overlap between amyloid‐PET positive vs. negative groups at the highest tertile of CSVD. No significant interaction was found between CSVD and any plasma p‐tau181 assay on amyloid‐PET positivity (all p>0.2, Figure1B).ConclusionOur findings suggest that individuals with a high burden of CSVD are at risk for incorrect Abeta‐42/40 ratio on certain assay platforms but not others. No interaction was found between CSVD and any plasma p‐tau181 assay on amyloid‐PET positivity. Further research in diverse cohorts with a high burden of CSVD is warranted to inform appropriate use of these blood assays and unravel mechanisms of this unexpected finding.