Contributions of rare and common variation to early-onset and atypical dementia risk

We collected and analyzed genomic sequencing data from individuals with clinician- diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients reported Caucasian, non-Hispanic ethnicity and six reported as African American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score was calculated for Alzheimer’s patients in the total cohort and compared to the scores of a late-onset Alzheimer’s cohort and a control set. Patients with early-onset Alzheimer’s had higher non- APOE polygenic risk scores than patients with late onset Alzheimer’s, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding for genomes sequenced at HudsonAlpha was generously provided by the Daniel Foundation of Alabama and donors to the HudsonAlpha Foundation Memory and Mobility Fund. Additional funding was provided by NIH grant R00AG068271 (J.N.C.), and NIH grant 5P20AG068024 (E.D.R., D.S.G., M.N.L, J.N.C., and J.W.T.). ### 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: IRB of University of Alabama at Birmingham gave ethical approval for tis 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I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data from the first 32 participants enrolled in this study are deposited at NIAGADS under project NG00082 - UAB/HudsonAlpha Families with Neurodegenerative Diseases. Note to reviewers: data for all other participants as well as for participants in the UAB ADRC study (a subset of late-onset cases) will be deposited to NIAGADS and made publicly available. Control sample data is available from HudsonAlpha CSER study(dbGap study accession number: phs001089.v3.p1) and from ADSP (NIAGIDS accession number: [NG00067][1].v9). [1]: /lookup/external-ref?link_type=GEN&access_num=NG00067&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F08%2F2023.02.06.23285383.atom