A study of gene expression in the living human brain

A central goal of neuroscience is to advance knowledge of the molecular basis of human brain function. Most molecular studies of the human brain have been performed using tissue from postmortem brain donors rather than living people. The assumption underlying this practice - which had never been rigorously tested prior to this report - is that the postmortem human brain is an appropriate proxy for the living human brain at the molecular level. Here, this assumption is thoroughly challenged for the first time by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples. Vast differences in gene expression were found between the living and postmortem human brain. Expression levels differed significantly for nearly 80% of genes, and this finding was not a consequence of any potential technical or biological confounders of the gene expression data. Postmortem brain gene expression signatures of Alzheimer's disease, schizophrenia, Parkinson's disease, bipolar disorder, and autism spectrum disorder were shown to be inaccurate representations of disease processes occurring in the living brain. In light of these findings, the use of postmortem tissue as a proxy for living tissue in human brain research should be reconsidered. To advance knowledge of the molecular basis of human brain function, the study of tissue from living people should be prioritized. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement National Institute of Aging (R01AG069976). The Michael J. Fox Foundation (Grant 18232), National Institute of Mental Health (R01MH109897). ### 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: All human subjects research was carried out under STUDY-13-00415 of the Human Research Protection Program at the Icahn School of Medicine at Mount Sinai. Research participants in the living cohort provided informed consent for sample collection, genomic profiling, clinical data extraction from medical records, and public sharing of de-identified data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 Upon publication in a peer-reviewed journal (1) all consented data used will be deposited in a public repository and (2) code for reproducing results from deposited data will be provided on a GitHub.