CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals
Tijms, Betty M. (Amsterdam University Medical Center (UMC))
Gobom, Johan (University of Gothenburg)
Teunissen, Charlotte E (Amsterdam University Medical Center (UMC))
Dobricic, Valerija (University of Lübeck)
Tsolaki, Magda (AHEPA University Hospital (Grècia))
Verhey, Frans (Maastricht University)
Popp, Julius (University of Zürich)
Martinez-Lage, Pablo (Fundación CITA-Alzhéimer Fundazioa (San Sebastián, País Basc))
Vandenberghe, Rik (KU Leuven. Department of Neurosciences)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Molinuevo, José Luis (Hospital Clínic i Provincial de Barcelona)
Engelborghs, Sebastiaan (Universitair Ziekenhuis Brussel)
Freund-Levi, Yvonne (Karolinska Institutet (Estocolm, Suècia). Department of Neurobiology, Care Sciences and Society)
Froelich, Lutz (University of Heidelberg. Department of Geriatric Psychiatry)
Bertram, Lars (University of Oslo. Department of Psychology)
Lovestone, Simon (University of Oxford)
Streffer, Johannes Rolf (AC Immune SA)
Vos, Stephanie J.B (Maastricht University)
Blennow, Kaj (University of Gothenburg)
Scheltens, Philip (Amsterdam University Medical Center (UMC))
Zetterberg, Henrik (UCL Institute of Neurology (Regne Unit). UK Dementia Research Institute)
Visser, Pieter Jelle (Karolinska Institutet (Estocolm, Suècia). Department of Neurobiology, Care Sciences and Society)
Universitat Autònoma de Barcelona

Date:	2021
Abstract:	We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p-tau and amyloid β 1-42 (Aβ42) CSF analysis showed that in the hyperplasticity subtype p-tau increased (β = 2. 6 pg/mL per year, p = 0. 01) and Aβ42 decreased over time (β = -4. 4 pg/mL per year, p = 0. 03), in the innate immune activation subtype p-tau increased (β = 3. 1 pg/mL per year, p = 0. 01) while in the blood-brain barrier dysfunction subtype Aβ42 decreased (β = -3. 7 pg/mL per year, p = 0. 009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alzheimer's disease ; Cerebrospinal fluid proteomics ; Risk factors ; Cognitive functioning ; Amyloid beta ; Tau
Published in:	Proteomes, Vol. 9 (august 2021) , ISSN 2227-7382

DOI: 10.3390/proteomes9030036
PMID: 34449748

15 p, 1.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles