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Continuous β-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity.
Sophie E Mastenbroek1, Arianna Sala1, David Vállez García1
1From the Department of Radiology and Nuclear Medicine (S.E.M., D.V.G., L.L., L.P., A.M.W., F.B., L.E.C.), Vrije Universiteit Amsterdam, Amsterdam University Medical Center, location VUmc; Amsterdam Neuroscience (S.E.M., D.V.G., L.L., L.P., A.M.W., F.B., L.E.C.), Brain Imaging, the Netherlands; Clinical Memory Research Unit (S.E.M., G.S., O.H., R.O., L.E.C.), Department of Clinical Sciences Malmö, Lund University; Division of Clinical Geriatrics (A.S., M. Bucci, A.K.N., E.R.-V.), Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Coma Science Group (A.S.), GIGA-Consciousness, University of Liège; Centre du Cerveau2 (A.S.), University Hospital of Liège, Belgium; Barcelonaβeta Brain Research Center (BBRC) (M.S., G.S., J.D.G.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (M.S., J.D.G.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (M.S., J.D.G.), Instituto de Salud Carlos III, Madrid; Universitat Pompeu Fabra (M.S.), Barcelona, Spain; Brain Research Center (I.L.A.), Amsterdam, the Netherlands; IXICO (R.W.), London; Centre for Clinical Brain Sciences (C.R.), University of Edinburgh, United Kingdom; Ace Alzheimer Center Barcelona (M. Boada), Universitat Internacional de Catalunya, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED) (M. Boada), Instituto de Salud Carlos III, Madrid, Spain; Alzheimer Center Amsterdam (P.J.V., R.O.), Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc; Amsterdam Neuroscience (P.J.V.), Neurodegeneration; Alzheimer Center Limburg (P.J.V.), School for Mental Health and Neuroscience, Maastricht University, the Netherlands; Division of Neurogeriatrics (P.J.V.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Theme Inflammation and Aging (M. Bucci, A.K.N.), Karolinska University Hospital, Stockholm, Sweden; GE Healthcare (G.F.), Amersham, United Kingdom; Memory Clinic (O.H.), Skåne University Hospital, Malmö, Sweden; and Centre for Medical Image Computing (F.B.), and Queen Square Institute of Neurology, UCL, London, United Kingdom.
A new continuous model quantifies beta-amyloid (Aβ) imbalance between soluble and aggregated forms using CSF and PET biomarkers. This Aβ-aggregation score reveals disease heterogeneity and predicts cognitive trajectories.
Area of Science:
- Neuroscience
- Biomarker Discovery
- Alzheimer's Disease Research
Background:
- Discrepancies between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for beta-amyloid (Aβ) may indicate varying Aβ species (soluble vs. aggregated).
- Previous studies often used binary cutoffs for CSF/PET Aβ discordance, losing information on the extent of imbalance and potential disease heterogeneity.
Purpose of the Study:
- To develop and validate a continuous model for quantifying the imbalance between soluble and aggregated Aβ pools using CSF and PET data.
- To identify factors influencing this Aβ imbalance.
- To examine the association between the Aβ imbalance measure and cognitive trajectories in individuals with and without cognitive impairment.
Main Methods:
- A hyperbolic regression model was applied to baseline CSF-Aβ42 and global Aβ-PET data from 822 individuals (ADNI cohort).
- A participant-specific Aβ-aggregation score was derived, representing the balance between soluble and aggregated Aβ.
- Linear models assessed contributing factors (methodological, demographic, CSF biomarkers, vascular burden), and linear mixed models evaluated predictive associations with cognitive functioning. Validation was performed in an independent cohort (383 individuals).
Main Results:
- The continuous imbalance model demonstrated high fit (pseudo-R² = 0.94) across both cohorts, CSF kits, and PET tracers.
- Aβ-aggregation scores were associated with ventricular volume, sex, APOE-ε4 carriership, CSF p-tau and t-tau levels, baseline executive functioning, and global cognitive decline.
- Key associations, including with APOE-ε4 and CSF t-tau, were replicated in the validation cohort.
Conclusions:
- A novel, continuous model accurately quantifies Aβ imbalance (soluble vs. aggregated) using CSF and PET biomarkers in independent cohorts.
- Aβ-aggregation scores reflect disease heterogeneity, correlating with genetic factors (APOE-ε4) and AD-associated CSF biomarkers beyond methodological influences.
- The Aβ-aggregation score shows potential as a continuous measure for understanding disease variability and predicting cognitive trajectories in Alzheimer's disease.
