Continuous β-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity

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• dc.contributor.author Mastenbroek, Sophie E.
• dc.contributor.author Gispert López, Juan Domingo
• dc.contributor.author Alzheimer's Disease Neuroimaging Initiative on behalf of the AMYPAD consortium
• dc.date.accessioned 2025-07-10T06:10:02Z
• dc.date.available 2025-07-10T06:10:02Z
• dc.date.issued 2024
• dc.description.abstract Background and objectives: Discordance between CSF and PET biomarkers of β-amyloid (Aβ) might reflect an imbalance between soluble and aggregated species, possibly reflecting disease heterogeneity. Previous studies generally used binary cutoffs to assess discrepancies in CSF/PET biomarkers, resulting in a loss of information on the extent of discordance. In this study, we (1) jointly modeled Aβ-CSF/PET data to derive a continuous measure of the imbalance between soluble and fibrillar pools of Aβ, (2) investigated factors contributing to this imbalance, and (3) examined associations with cognitive trajectories. Methods: Across 822 cognitively unimpaired (n = 261) and cognitively impaired (n = 561) Alzheimer's Disease Neuroimaging Initiative individuals (384 [46.7%] females, mean age 73.0 ± 7.4 years), we fitted baseline CSF-Aβ42 and global Aβ-PET to a hyperbolic regression model, deriving a participant-specific Aβ-aggregation score (standardized residuals); negative values represent more soluble relative to aggregated Aβ and positive values more aggregated relative to soluble Aβ. Using linear models, we investigated whether methodological factors, demographics, CSF biomarkers, and vascular burden contributed to Aβ-aggregation scores. With linear mixed models, we assessed whether Aβ-aggregation scores were predictive of cognitive functioning. Analyses were repeated in an early independent validation cohort of 383 Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study individuals (224 [58.5%] females, mean age 65.2 ± 6.9 years). Results: The imbalance model could be fit (pseudo-R2 = 0.94) in both cohorts, across CSF kits and PET tracers. Although no associations were observed with the main methodological factors, lower Aβ-aggregation scores were associated with larger ventricular volume (β = 0.13, p < 0.001), male sex (β = -0.18, p = 0.019), and homozygous APOE-ε4 carriership (β = -0.56, p < 0.001), whereas higher scores were associated with increased uncorrected CSF p-tau (β = 0.17, p < 0.001) and t-tau (β = 0.16, p < 0.001), better baseline executive functioning (β = 0.12, p < 0.001), and slower global cognitive decline (β = 0.14, p = 0.006). In the validation cohort, we replicated the associations with APOE-ε4, CSF t-tau, and, although modestly, with cognition. Discussion: We propose a novel continuous model of Aβ CSF/PET biomarker imbalance, accurately describing heterogeneity in soluble vs aggregated Aβ pools in 2 independent cohorts across the full Aβ continuum. Aβ-aggregation scores were consistently associated with genetic and AD-associated CSF biomarkers, possibly reflecting disease heterogeneity beyond methodological influences.
• dc.format.mimetype application/pdf
• dc.identifier.citation Mastenbroek SE, Sala A, Vállez García D, Shekari M, Salvadó G, Lorenzini L, et al. Continuous β-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity. Neurology. 2024 Jul 9;103(1):e209419. DOI: 10.1212/WNL.0000000000209419
• dc.identifier.doi http://dx.doi.org/10.1212/WNL.0000000000209419
• dc.identifier.issn 0028-3878
• dc.identifier.uri http://hdl.handle.net/10230/70874
• dc.language.iso eng
• dc.publisher Wolters Kluwer (LWW)
• dc.relation.ispartof Neurology. 2024 Jul 9;103(1):e209419
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/115952
• dc.rights Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Alzheimer, Malaltia d'
• dc.title Continuous β-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion