{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T22:09:46Z","timestamp":1788905386159,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,4]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"crossref","award":["AARG-25-1472103"],"award-info":[{"award-number":["AARG-25-1472103"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute on Aging (NIA), NIH","award":["R01AG071683 and U54AG054349"],"award-info":[{"award-number":["R01AG071683 and U54AG054349"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1T32GM136624-01"],"award-info":[{"award-number":["1T32GM136624-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Interindividual heterogeneity in Alzheimer\u2019s disease (AD) remains poorly understood, as disparate single-cell studies leave it unclear whether findings reflect shared architecture or dataset-specific idiosyncrasies. Here, we present panAD, a transcriptomic atlas of &gt;3 million nuclei from 791 individuals across 13 studies, spanning AD, mild cognitive impairment, and cognitively normal aging. AD converges on a reproducible, cell-type-specific molecular architecture: co-expression modules track neuropathology and cognitive decline; GWAS risk genes act predominantly as downstream targets of transcription factor hubs such as microglial\n                  <jats:italic>SPI1<\/jats:italic>\n                  ; intercellular communication is remodeled with disease stage; and sex differences concentrate in microglial immune-activation programs. To model patient-level transcriptomic heterogeneity, we developed the Multi-seed Optimization of Neural Embeddings for subTyping (MONET) framework, in which a masked variational autoencoder applied to covariate-adjusted, multi-cell-type profiles resolves four subtypes (Metal-Ion Stress, Neuroinflammatory, Synaptic Integrity, and Tissue Remodeling) that dissociate neuropathological burden from cognitive impairment and nominate predominantly non-overlapping candidate therapeutics. Finally, Stellar Atlas provides an AI-native conversational interface to the atlas.\n                <\/jats:p>","DOI":"10.64898\/2026.09.03.747935","type":"posted-content","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:15:13Z","timestamp":1788534913000},"source":"Crossref","is-referenced-by-count":0,"title":["An Integrated Single-Nucleus Atlas Resolves Cell-Type-Specific Programs and Molecular Subtypes in Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7797-620X","authenticated-orcid":false,"given":"Negin","family":"Rahimzadeh","sequence":"first","affiliation":[{"name":"Mathematical, Computational, and Systems Biology (MCSB) Program, University of California, Irvine, CA, USA"},{"name":"Center for Complex Biological Systems (CCBS), University of California, Irvine, CA, USA"},{"name":"Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, CA, USA"},{"name":"Department of Systems Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Morabito","sequence":"additional","affiliation":[{"name":"Mathematical, Computational, and Systems Biology (MCSB) Program, University of California, Irvine, CA, USA"},{"name":"Center for Complex Biological Systems (CCBS), University of California, Irvine, CA, USA"},{"name":"Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, CA, USA"},{"name":"Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saniya","family":"Khullar","sequence":"additional","affiliation":[{"name":"Allen Institute for Brain Science, Seattle, Washington, USA"},{"name":"Wellcome Sanger Institute, Hinxton, England"},{"name":"Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zechuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, CA, USA"},{"name":"Department of Systems Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenkun","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3762-2746","authenticated-orcid":false,"given":"Vivek","family":"Swarup","sequence":"additional","affiliation":[{"name":"Mathematical, Computational, and Systems Biology (MCSB) Program, University of California, Irvine, CA, USA"},{"name":"Center for Complex Biological Systems (CCBS), University of California, Irvine, CA, USA"},{"name":"Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, CA, USA"},{"name":"Department of Systems Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026090814450498000_2026.09.03.747935v1.1","doi-asserted-by":"crossref","unstructured":"Twiss, E. , McPherson, C. & Weaver, D.F . 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