Epigenetic clock acceleration is linked to earlier onset and phenoconversion age in REM sleep behavior disorder

Rapid-eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA-methylation-age (DNAm-age) is an epigenetic clock that could reflect biological aging. We evaluated whether RBD age-at-onset/phenoconversion are associated with DNAm-age-acceleration in 162 RBD patients. We found an association of DNAm-age-acceleration with RBD age-at-onset at baseline (P=2.59e-08) and at follow-up (N=45; P=9.73e-06). RBD patients with faster aging had 4.6 years earlier onset than patients with slow/normal aging. Similarly, earlier age-at-phenoconversion was associated with DNAm-age-acceleration (N=53; P=1.26e-04). We demonstrated that epigenetic clock acceleration is linked with an earlier RBD age-at-onset and, hence with earlier phenoconversion. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the G. Harris Sheppard Fund for Research in Parkinson’s and other Neurodegenerative Diseases (ER), Canadian Consortium on Neurodegeneration in Aging (ER, ZGO), the Blidner Family Foundation (NPV), and the McLaughlin Accelerator Grants in Genomic Medicine (ER, ZGO, AEL, RP). ZGO is supported by the Fonds de recherche du Quebec - Sante (FRQS) Chercheurs-boursiers award, in collaboration with Parkinson Quebec, and is a William Dawson Scholar. KS is supported by a post-doctoral fellowship from the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives initiative (HBHL), FRQS post-doctoral fellowship and McKerracher Award. ### 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: Ethics committee/IRB of the University Health Network (UHN) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 results are reported in the tables or attached to the supplementary data.