Cross-omics integration shows cortex-wide synaptic dysfunction at later stages of Alzheimer disease

Clinical and molecular heterogeneity of Alzheimer disease (AD) is increasingly recognized as a major factor impacting the diagnosis, the design of therapeutic interventions and clinical trials, and therefore possibly delaying the development of effective treatments for AD. We sought to determine whether cross-omics integration reveals molecular profiles of AD with clinical and biological relevance. By leveraging cross-omics approaches, we integrated high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles from AD and control cases from multiple cortical regions and cohorts. We identified four distinct molecular profiles in which a specific profile was associated with significantly higher Clinical Dementia Rating (CDR) at death, shorter survival after onset, more severe neurodegeneration and astrogliosis, and decreased levels of metabolomic profiles. Its molecular signatures show significant dysregulation of synaptic genes indicating neuron/synapse losses and dysfunction at later stages of AD, and present in multiple cortical regions. Among other molecules, we found that the expression of alpha-synuclein ( SNCA ) and SNAP25 were downregulated in this profile. Overall, our results suggest that AD has a more prominent synaptic loss and dysfunction associated with worse cognition. These novel molecular findings open the possibility for new biomarkers for the molecular staging of AD and potential therapeutic targets to ameliorate cognitive decline and AD progression. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Knight Alzheimer Disease Research Center at Washington University School of Medicine through the National Institute on Aging (NIA: grant no. P30 AG066444 - JCM), Healthy Aging and Senile Dementia (HASD: grant no. P01AG003991 - JCM), and Antecedent Biomarkers for Alzheimer Disease: The Adult Children Study (ACS: grant no. P01AG026276 - JCM). This work was supported by grants from the National Institutes of Health: NIA R01AG057777 (OH), K01AG046374 (CMK), R56AG067764 (OH), the Chan Zuckerberg Initiative (CMK). O.H. is an Archer Foundation Research Scientist. A.M.E. is a scholar recipient of the Knight ADRC Research Education Component (NIA: grant no. P30 AG066444). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. ROSMAP (RNA-seq) Study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNAseq), R01AG48015 (monocyte RNAseq) RF1AG57473 (single nucleus RNAseq), U01AG32984 (genomic and whole exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161(TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu. Study data were provided through NIA grant 3R01AG046171-02S2 awarded to Rima Kaddurah-Daouk at Duke University, based on specimens provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, where data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. Alzheimer's Disease Metabolomics Consortium (ADMC) The results published here are in whole or partly based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). Metabolomics data is provided by the Alzheimer's Disease Metabolomics Consortium (ADMC) and funded wholly or in part by the following grants and supplements: NIA R01AG046171, RF1AG051550, 3U01AG024904-09S4, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744, and FNIH: #DAOU16AMPA awarded to Dr. Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions. As such, the investigators within the ADMC, not listed specifically in this publication's author's list, provided data along with its pre-processing and prepared it for analysis but did not participate in the analysis or writing of this manuscript. A complete listing of ADMC investigators can be found at: https://sites.duke.edu/adnimetab/team/. MSBB The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org/). These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. Proteomics data were provided by Dr. Levey from Emory University based on postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank provided by Dr. Eric Schadt from Mount Sinai School of Medicine. ### 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 used openly available human data from the Knight ADRC located at the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) (https://www.niagads.org/datasets) as well as data from other studies located at the AD Knowledge Portal (https://adknowledgeportal.synapse.org/). Frozen postmortem parietal lobe tissue samples from Knight Alzheimer Disease Research Center (Knight ADRC) participants, collected with informed consent for research use, were provided by the Knight ADRC Neuropathology Core. Analysis of these samples was approved by the institutional review board of Washington University in St. Louis. 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 Transcriptomics data from the Knight ADRC are available by request from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) with accession number [ng00083][1] (https://www.niagads.org/datasets/ng00083). Proteomics data from the Knight ADRC donors are available at the NIAGADS Knight ADRC collection with accession number [ng00102][2] (https://www.niagads.org/datasets/ng00102). Metabolomics data from the Knight ADRC are available at the NIAGADS Knight ADRC collection with accession number [NG00113][3] (https://dss.niagads.org/datasets/ng00113/). The single nucleus data from the Knight ADRC are available at NIAGADS Knight ADRC collection with accession number [NG00108][4] (https://dss.niagads.org/datasets/ng00108/). MSBB transcriptomics and proteomics data are publicly available at Synapse under Synapse IDs syn3157743 (https://www.synapse.org/#!Synapse:syn3157743) and syn25006650 (https://www.synapse.org/#!Synapse:syn25006650) respectively. ROSMAP transcriptomics and metabolomics data are publicly available at Synapse under Synapse IDs syn17008934 (https://www.synapse.org/#!Synapse:syn17008934) and syn25878459 (https://www.synapse.org/#!Synapse:syn25878459) respectively. [1]: /lookup/external-ref?link_type=GEN&access_num=ng00083&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F13%2F2022.12.10.22283295.atom [2]: /lookup/external-ref?link_type=GEN&access_num=ng00102&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F13%2F2022.12.10.22283295.atom [3]: /lookup/external-ref?link_type=GEN&access_num=NG00113&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F13%2F2022.12.10.22283295.atom [4]: /lookup/external-ref?link_type=GEN&access_num=NG00108&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F13%2F2022.12.10.22283295.atom