Loss of Y is associated with multi-omic changes in immune cells from Alzheimer’s disease patients

Alzheimer’s disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of Y (LOY) in leukocytes is more prevalent in AD patients. We studied DNA methylation, gene expression and other epigenetic changes in monocytes and granulocytes with and without LOY from male AD patients and controls. New candidate genes were identified and numerous genes already implicated in AD pathogenesis were confirmed. We show that multi-omics of leukocytes can define AD candidate genes and we strengthen the role of LOY in disease development. The LOY-associated differences in DNA methylation levels were predominantly observed in regulatory regions, and supported by expression analysis showing down-regulation of immune genes. The single-cell transcriptomics highlighted that the AD patient-specific immune activation dominates over LOY-specific activation. Our findings agree with the hypothesis that age-related dysfunction of immune cells contribute to AD and that LOY is reflected by higher-level epigenetic changes with an AD-specific pattern. ### Competing Interest Statement J.P.D is a cofounder and shareholder in Cray Innovation AB. The remaining authors declare that they have no competing interests. ### Funding Statement This study was supported by grants from the Foundation for Polish Science under the International Research Agendas Programme (grant number MAB/2018 /6; co-financed by the European Union under the European Regional Development Fund), Swedish Heart-Lung Foundation (grant number 20210051), the Swedish Research Council (grant number 2020-02010), Swedish Cancer Society, Hjarnfonden, and Alzheimerfonden to J.P.D. ### 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: The study was approved by the local research ethics committee in Uppsala, Sweden (Regionala Etikprovningsnamnden i Uppsala (EPN) and the Bioethical Committee of the Regional Medical Chamber in Krakow, Poland. All participants or next of kin have given their written informed consent to participate. The study was conducted according to the guidelines of the Declaration of Helsinki. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * LOY : loss of chromosome Y AD : Alzheimer’s disease DMP : differentially methylated probe DEG : differentially expressed gene DMG : differentially methylated gene