ABSTRACT Molecular investigations of Alzheimer’s disease and related dementias over the past decade have largely relied on postmortem specimens due to the inaccessibility of the brain in living people. At least two serious limitations are inherent to this framework. First, the molecular impact of death and the preceding agonal process on the human brain are unknown. This uncertainty looms over the field as a potential confounder of virtually all modern neurobiological studies of Alzheimer’s disease and related dementias in humans. Second, profiling the brain postmortem decouples molecular biology from deep neuropsychiatric assessment and neuroimaging. As a result, a holistic narrative of how molecular biology influences brain structure and functions dysregulated in Alzheimer’s disease and related dementias has failed to emerge. These serious limitations could be addressed by the ability to molecularly profile the brain in living people. Here, we address these serious limitations through the Living Brain Project, wherein we perform comprehensive multiomic molecular profiling of living and postmortem human brain tissue. The primary innovation of the LBP is a safe, scalable procedure for sampling the dorsolateral prefrontal cortex (DLPFC) in living people. We will profile the genome, transcriptome (bulk and single-cell), proteome, metabolome and lipidome in over 500 living and postmortem human subjects. Analyses of this data will identify molecular signatures differentiating the living and postmortem states. We will harness these insights to determine the extent to which they have confounded postmortem studies of Alzheimer’s disease and related dementias. Finally, we will integrate these multiomics datasets with neuroimaging and neurocognitive assessments from the same individuals. To our knowledge, the proposed experiments and analyses will comprise (1) the largest molecular study of the living human brain, (2) the largest molecular comparison of living and postmortem human brain tissues, and (3) the largest effort pairing multiomic molecular profiles of the brain with neuroimaging and deep neurocognitive phenotyping from the same living individuals. We anticipate fundamental advances in knowledge of human brain biology and the pathogenesis of Alzheimer’s disease and related dementias will be made by making this rich dataset freely available to scientific community.

NARRATIVE The inaccessibility of the brain in living people has confined molecular investigations of neuropsychiatric traits to postmortem tissue. Here, we address critical limitations that arise from this framework through (1) comprehensive, multiomic molecular profiling of living and postmortem human brain tissue and (2) integrating multiomics data with neuroimaging and neurocognitive data from the same individuals. At the center of this proposal is the Living Brain Project (LBP), wherein we survey a vast data landscape in individuals undergoing deep brain stimulation, including molecular data derived from bilateral biopsies from the dorsolateral prefrontal cortex. We anticipate fundamental advances in our understanding of the human brain will be made not only by the analyses proposed here but also by making this rich resource available to the larger scientific community.