Continuous β-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity
Sophie E Mastenbroek, Arianna Sala, David Vállez García, Mahnaz Shekari, Gemma Salvadó, Luigi Lorenzini, Leonard Pieperhoff, Alle Meije Wink, Isadora Lopes Alves, Robin Wolz, Craig Ritchie, Merçé Boada, Pieter Jelle Visser, Marco Bucci, Gill Farrar, Oskar Hansson, Agneta Nordberg, Rik Ossenkoppele, Frederik Barkhof, Juan Domingo Gispert, Elena Rodriguez‐Vieitez, Lyduine E. Collij
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: 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: -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.