{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:51:00Z","timestamp":1787010660417,"version":"build-2736575974"},"posted":{"date-parts":[[2025,6,3]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer\u2019s disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, \u03b2-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (\u03b2-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts:\n                  <jats:italic>STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP,<\/jats:italic>\n                  and\n                  <jats:italic>SYT7<\/jats:italic>\n                  . While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of \u03b2-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, \u03b2-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43\u2013depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease\n                <\/jats:p>","DOI":"10.1101\/2025.05.30.656396","type":"posted-content","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:25:15Z","timestamp":1749014715000},"source":"Crossref","is-referenced-by-count":7,"title":["Molecular subtyping based on hippocampal cryptic exon burden reveals proteome-wide changes associated with TDP-43 pathology across the spectrum of LATE and Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Adam N.","family":"Trautwig","sequence":"first","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anantharaman","family":"Shantaraman","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingee","family":"Chung","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2947-7606","authenticated-orcid":false,"given":"Eric B.","family":"Dammer","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyan","family":"Ping","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duc M.","family":"Duong","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5296-8051","authenticated-orcid":false,"given":"Michael E.","family":"Ward","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA"},{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Glass","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan I.","family":"Levey","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary T.","family":"McEachin","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4507-624X","authenticated-orcid":false,"given":"Nicholas T.","family":"Seyfried","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Department of 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