Abstract
Genetic factors play a major role in Alzheimer's disease (AD) pathology, but biological mechanisms through which these factors contribute to AD remain elusive. Using a cerebrospinal fluid (CSF) proteomic approach, we examined associations between polygenic risk scores for AD (PGRS) and CSF proteomic profiles in 250 individuals with normal cognition, mild cognitive impairment, and AD-type dementia from the Alzheimer's Disease Neuroimaging Initiative. Out of 412 proteins, 201 were associated with PGRS. Hierarchical clustering analysis on proteins associated with PGRS at different single-nucleotide polymorphism p-value inclusion thresholds identified 3 clusters: (1) a protein cluster correlated with highly significant single-nucleotide polymorphisms, associated with amyloid-beta pathology and complement cascades; (2) a protein cluster associated with PGRS additionally including variants contributing to modest risk, involved in neural injury; (3) a protein cluster that also included less strongly associated variants, enriched with cytokine-cytokine interactions and cell adhesion molecules. These findings suggest that CSF protein levels reflect varying degrees of genetic liability for AD and may serve as a tool to investigate biological mechanisms in AD.
| Original language | English |
|---|---|
| Pages (from-to) | 144.e1-144.e15 |
| Number of pages | 15 |
| Journal | Neurobiology of Aging |
| Volume | 93 |
| Early online date | 24 Mar 2020 |
| DOIs | |
| Publication status | Published - Sept 2020 |
Funding
Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. Analyses were supported by the EU-PRISM Project (Psychiatric Ratings using Intermediate Stratified Markers, www.prism-project.eu ), which received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations (EFPIA). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) , National Institutes of Health (Grant U01 AG024904 ) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012 ). 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's Association; Alzheimer'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'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. The authors thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips were funded by the French National Foundation on Alzheimer's disease and related disorders. The European Alzheimer's disease Initiative (EADI) was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2, and the Lille University Hospital. The Genetic and Environmental Risk in AD consortium (GERAD) was supported by the Medical Research Council (grant no. 503480 ), Alzheimer's Research UK (grant no. 503176 ), the Wellcome Trust (grant no. 082604/2/07/Z ), and German Federal Ministry of Education and Research (i.e., Bundesministerium für Bildung und Forschung, BMBF): Competence Network Dementia (CND) grant no. 01GI0102 , 01GI0711 , 01GI0420 . The Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE) was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. The Alzheimer Disease Genetics Consortium (ADGC) was supported by the NIH/NIA grants U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC–10–196728. Charlotte E. Teunissen received grant funding from the European Commission, the Dutch Research Council (ZonMW), Association of Frontotemporal Dementia/Alzheimer's Drug Discovery Foundation, Alzheimer Netherlands. Charlotte E. Teunissen has functioned in advisory boards of Fujirebio and Roche, received nonfinancial support in the form of research consumables from ADx Neurosciences and Euroimmun, performed contract research or received grants from Probiodrug, Janssen prevention center, Boehringer, Brains online, Axon Neurosciences, EIP pharma, Roche. Philip Scheltens has acquired grant support (for the institution) from Piramal. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche (diagnostics). He is PI of studies with Probiodrug and EIP Pharma. Yolande AL Pijnenburg received a personal fellowship from the Dutch brain foundation. Pieter Jelle Visser serves as an advisory board member of Eli-Lilly, is consultant for Janssen, and has received grants from GE healthcare and Biogen. Pieter Jelle Visser received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant: 115372). Betty M. Tijms received grant funding from the ZonMW Memorabel grant program #73305056 and #733050824. All other authors report no disclosures. Funding sources had no role in design and conduct of the study, data collection, data analysis, data interpretation, or in writing or approval of this report. Written informed consent was obtained from all participants.
| Funders | Funder number |
|---|---|
| AGEs | N01–AG–12100 |
| Alzheimer Disease Genetics Consortium | U24 AG021886, U01 AG016976, U01 AG032984 |
| Cohorts for Heart and Aging Research in Genomic | |
| DOD ADNI | |
| Dutch Brain Foundation | |
| EIP Pharma | |
| EU-PRISM | |
| EU/EFPIA | 115372, 733050824, 73305056 |
| Erasmus University | |
| European Alzheimer's disease Initiative | |
| French National Foundation | |
| GE healthcare and Biogen | |
| Janssen prevention center | |
| Piramal | |
| National Institutes of Health | U01 AG024904 |
| U.S. Department of Defense | W81XWH-12-2-0012 |
| National Institute on Aging | R01 AG033193, AG081220 |
| National Heart, Lung, and Blood Institute | R01HL105756 |
| National Institute of Biomedical Imaging and Bioengineering | |
| Alzheimer's Association | ADGC–10–196728 |
| Roche | |
| Biogen | |
| University of Southern California | |
| Alzheimer's Disease Neuroimaging Initiative | |
| Northern California Institute for Research and Education | |
| Wellcome Trust | 082604/2/07/Z |
| European Federation of Pharmaceutical Industries and Associations | |
| Université de Lille | |
| Medical Research Council | 503480 |
| European Commission | |
| Institut national de la santé et de la recherche médicale | |
| ZonMw | |
| Alzheimer’s Research UK | 503176 |
| Bundesministerium für Bildung und Forschung | 01GI0711, 01GI0420, 01GI0102 |
| Erasmus Medisch Centrum | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Labex | |
| Horizon 2020 | |
| Innovative Medicines Initiative | 115916 |
| Hjartavernd | |
| Institute Pasteur De Lille | |
| Centre hospitalier régional universitaire de Lille |
Keywords
- Alzheimer's disease (AD)
- Cell adhesion molecules
- Cerebrospinal fluid (CSF)
- Complement cascades
- Cytokines
- Polygenic risk scores (PGRS)
