{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:47Z","timestamp":1792790447298,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,8]]},"group-title":"Neuroscience","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"the National Natural Science Foundation of China","award":["32530027"],"award-info":[{"award-number":["32530027"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the Key R&D Program of Zhejiang Province","award":["2024C03098"],"award-info":[{"award-number":["2024C03098"]}]},{"name":"the Key R&D Program of Zhejiang Province","award":["2025C01120"],"award-info":[{"award-number":["2025C01120"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Reduced muscle strength is associated with cognitive decline and Alzheimer\u2019s disease (AD), suggesting that skeletal-muscle aging and AD-related neurodegeneration may share biological mechanisms. Vascular dysfunction, immune activation, and extracellular-matrix remodeling have been implicated in both tissues, but the extent of shared cellular and molecular programs remains unclear. We investigated cross-tissue transcriptional programs in aging skeletal muscle and AD-related brain tissue and evaluated whether related signals are detectable in peripheral blood.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed independent, unpaired human transcriptomic datasets from skeletal muscle (23 donors), the SEA-AD middle temporal gyrus atlas (84 donors), and peripheral blood. Donor-aware models identified age-associated changes in muscle and transcriptomic changes across continuous pseudoprogression score (CPS) in brain. Cross-tissue comparisons focused on 30 brain donors within an early CPS window. Shared tissue-derived programs were assessed in peripheral blood mononuclear cells and independently tested in frailty bulk-blood and Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) whole-blood datasets. CellOracle simulations were used to prioritize candidate transcriptional regulators.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Aging muscle showed increased inflammatory, extracellular-matrix, and stromal communication programs. During early AD-related brain progression, vascular and immune populations showed increasing inflammatory and matrix-associated activity together with shifts in intercellular communication. Cross-tissue analysis identified six concordantly enriched pathways comprising 109 leading-edge genes in endothelial populations and four pathways comprising 51 genes in myeloid populations. Related peripheral-blood signatures varied across cohorts and cell types. However, in independent frailty and ADNI mild cognitive impairment and AD datasets, 23 of 30 predefined tissue-derived pathway-subset tests showed significant positive enrichment after false-discovery-rate correction, whereas individual gene-level bulk-blood associations did not survive correction. CellOracle analyses prioritized ETS2 and BHLHE40 as exploratory endothelial regulators whose simulated perturbation consistently reduced selected shared program scores across tissues.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Aging skeletal muscle and AD-related brain tissue exhibit convergent endothelial and myeloid inflammatory programs, with related pathway-level signals detectable in peripheral blood. These cross-tissue programs and candidate endothelial regulators provide testable hypotheses for mechanisms linking systemic aging, muscle dysfunction, and AD-related neurodegeneration.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.10.07.751107","type":"posted-content","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:55:18Z","timestamp":1791456918000},"source":"Crossref","is-referenced-by-count":0,"title":["Cross-Tissue Inflammatory Convergence Supports a Putative Muscle\u2013Brain Axis in Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9283-8589","authenticated-orcid":false,"given":"Andong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China"},{"name":"Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pathology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China"},{"name":"Nanhu Brain-computer Interface Institute, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijun","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pathology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"},{"name":"Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-chemical and Aging-related Injuries."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfeng","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaotian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"},{"name":"Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YiTing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pathology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 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Injuries."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fariba","family":"Ahmadizar","sequence":"additional","affiliation":[{"name":"Department of General Practice, Amsterdam University Medical Centre, Amsterdam, The Netherlands"},{"name":"Department of Epidemiology and Data Science, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Neuroscience Institute, Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology of First Affiliated Hospital and School 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