@article{f11dd7642b934f6fbc2727297b6821b5,
title = "CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals",
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(181)-tau and amyloid beta 1-42 (A beta 42) CSF analysis showed that in the hyperplasticity subtype p(181)-tau increased (beta = 2.6 pg/mL per year, p = 0.01) and A beta 42 decreased over time (beta = -4.4 pg/mL per year, p = 0.03), in the innate immune activation subtype p(181)-tau increased (beta = 3.1 pg/mL per year, p = 0.01) while in the blood-brain barrier dysfunction subtype A beta 42 decreased (beta = -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.",
keywords = "Alzheimer's disease, cerebrospinal fluid proteomics, risk factors, cognitive functioning, amyloid beta, tau, ASSOCIATION WORKGROUPS, DIAGNOSTIC GUIDELINES, NATIONAL INSTITUTE, RECOMMENDATIONS, IMPAIRMENT, REST, BIOMARKERS, DEMENTIA, CRITERIA, NEURONS",
author = "B.M. Tijms and J. Gobom and C. Teunissen and V. Dobricic and M. Tsolaki and F. Verhey and J. Popp and P. Martinez-Lage and R. Vandenberghe and A. Lleo and J.L. Molinuevo and S. Engelborghs and Y. Freund-Levi and L. Froelich and L. Bertram and S. Lovestone and J. Streffer and S. Vos and K. Blennow and P. Scheltens and H. Zetterberg and P.J. Visser and {Alzheimer's Disease Neuroimaging Initiative}",
note = "Funding Information: This research was funded by ZonMW Memorabel Grant programme, grant number #733050824; the Innovative Medicines Initiative Joint undertaking under EMIF grant number #115372; the European Research Council, grant number #681712; the Swedish research council, grant number #201802532; and the Alzheimerfonden, grant number #AF-930934. Statistical analyses were performed at the VUmc Alzheimer Center that is part of the neurodegeneration research program of the Neuroscience Campus Amsterdam. EMIF-AD MBD proteomic analyses were performed at the Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Sweden. The VUmc Alzheimer Center is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. ADNI data were used for this project of which collection and sharing was funded by the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-20012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer{\textquoteright}s Association; Alzheimer{\textquoteright}s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Conflicts of Interest: H.Z. has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. The other authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = sep,
day = "1",
doi = "10.3390/proteomes9030036",
language = "English",
volume = "9",
journal = "Proteomes",
publisher = "MDPI",
number = "3",
}