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Alzheimer’s disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325/335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association via at least 5 studies, while 63% of pathway terms have at least 50 studies providing a clear association with AD. Despite major technological advances, the same set of top-ranked pathways have been consistently related to AD for 30 years, including AD, immune system, metabolic pathways, cholinergic synapse, long-term depression, proteasome, diabetes, cancer, and chemokine signaling. AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results of this study can be explored at www.adpathways.org.

The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells. Integrated analysis and comparisons with healthy controls revealed extensive changes in the cellular composition and expression states in COVID-19 liver, reflecting hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis. We also observed Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas, resembling similar responses in liver injury in mice and in sepsis, respectively. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition was dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.

The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients' demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63 + intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies., Competing Interests: Competing Interests P.D., R.F., E.M.M., M.R., E.H.R., L.P., T.He., J.R., J.B., and S.W. are employees and stockholders at Nanostring Technologies Inc. D.Z., is a former employee and stockholder at NanoString Technologies. N.H., holds equity in BioNTech and Related Sciences. T.H.is an employee and stockholder of Prime Medicine as of Oct. 13, 2020. G.H. is an employee of Genentech as of Nov 16, 2020. R.N. is a founder, shareholder, and member of the board at Rhinostics Inc. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until July 31, 2020. From August 1, 2020, A.R. is an employee of Genentech. From October 19, 2020, O.R.-R is an employee of Genentech. P.C.S is a co-founder and shareholder of Sherlock Biosciences, and a Board member and shareholder of Danaher Corporation. A.K.S. reports compensation for consulting and/or SAB membership from Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, and Dahlia Biosciences. Z.G.J. reports grant support from Gilead Science, Pfizer, compensation for consulting from Olix Pharmaceuticals. Y.V.P. reports grant support from Enanta Pharmaceuticals, CymaBay Therapeutics, Morphic Therapeutic; consulting and/or SAB in Ambys Medicines, Morphic Therapeutics, Enveda Therapeutics, BridgeBio Pharma, as well as being an Editor – American Journal of Physiology-Gastrointestinal and Liver Physiology. GS reports consultant service in Alnylam Pharmaceuticals, Merck, Generon, Glympse Bio, Inc., Mayday Foundation, Novartis Pharmaceuticals, Quest Diagnostics, Surrozen, Terra Firma, Zomagen Bioscience, Pandion Therapeutics, Inc. Durect Corporation; royalty from UpToDate Inc., and Editor service in Hepatology Communications. P.R.T. receives consulting fees from Cellarity Inc., and Surrozen Inc., for work not related to this manuscript.