Blood-based multivariate methylation risk score for cognitive impairment and dementia

INTRODUCTION Given the established association between DNA methylation and the pathophysiology of dementia and its plausible role as a molecular mediator of lifestyle and environment, blood-derived DNA methylation data could enable early detection of dementia risk. METHODS In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in two independent cohorts of Alzheimer’s disease (AD) and Parkinson’s disease (PD). RESULTS We established a multivariate methylation risk score (MMRS) to identify the status of mild cognitive impairment (MCI) cross-sectionally, independent of age and sex. We further demonstrated significant predictive capability of this score for the prospective onset of cognitive decline in AD and PD. DISCUSSION Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported through a ZonMw Memorabel/Alzheimer Nederland Grant (733050516) to E.P. The current study was conducted as part of the EMIF-AD MBD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement number 115372, the resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies' in kind contribution. The analysis of the DNA methylation data was in part funded by a major project grant from the Alzheimer's Society UK (AS-PG-14-038) to KL, a project grant from the Medical Research Council (MRC) (MR/N027973/1) to KL as part of the EPI-AD consortium through the Joint Programme-Neurodegenerative Disease Research (JPND) initiative. We thank all participants and teams who contributed data to PPMI. PPMI, a public-private partnership, is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners including 4D Pharma, AbbVie, AcureX Therapeutics, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's (ASAP), Avid Radiopharmaceuticals, Bial Biotech, Biogen, BioLegend, Bristol Myers Squibb, Calico Life Sciences LLC, Celgene Corporation, DaCapo Brainscience, Denali Therapeutics, The Edmond J. Safra Foundation, Eli Lilly and Company, GE Healthcare, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Pharmaceuticals, Lundbeck, Merck & Co., Meso Scale Diagnostics LLC, Neurocrine Biosciences, Pfizer, Piramal Imaging, Prevail Therapeutics, F. Hoffmann‐La Roche and its affiliated company Genentech, Sanofi Genzyme, Servier, Takeda Pharmaceutical Company, Teva Neuroscience, UCB, Vanqua Bio, Verily Life Sciences, Voyager Therapeutics and Yumanity Therapeutics. 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][1]). 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. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * Aβ : amyloid-β AD : Alzheimer’s disease ADAS : Alzheimer’s disease assessment scale AUROC : area under the receiver operating curve CI : confidence interval CSF : cerebral spinal fluid EN : ElasticNet GO : gene ontology HR : hazard ratio HWE : Hardy-Weinberg equilibrium LDELTOTAL : Wechsler logical memory delay MAE : mean absolute error MAF : minor allele frequency MCI : mild cognitive impairments mQTL : methylation quantitative trait loci MMRS : multivariate methylation risk score MMSE : Mini Mental State Examination MPS : methylation profile score PCA : principal component analysis PD : Parkinson’s disease PGS : polygenic (risk) score p-tau : phosphorylated tau QC : quality control RAVLT : Rey’s auditory verbal learning test RF-RFE : random forest with recursive feature elimination SHAP : Shapley additive explanations SNP : single nucleotide polymorphism sPLS-DA : sparse partial least squares discriminant analysis TRABSCOR : trail making test part B time t-tau : total tau UTR : untranslated region. [1]: https://www.fnih.org