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Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although \u201cpure\u201d LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and\/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions (\u201csynergies\u201d) between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.<\/jats:p>","DOI":"10.1093\/jnen\/nlae032","type":"journal-article","created":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T17:31:37Z","timestamp":1713029497000},"page":"396-415","source":"Crossref","is-referenced-by-count":52,"title":["Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis"],"prefix":"10.1093","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6161-1265","authenticated-orcid":false,"given":"Peter T","family":"Nelson","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Kentucky , Lexington, Kentucky, USA"},{"name":"Department of Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7207-4696","authenticated-orcid":false,"given":"David W","family":"Fardo","sequence":"additional","affiliation":[{"name":"Department of Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"},{"name":"Department of Biostatistics, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"},{"name":"Department of Biostatistics, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khine Zin","family":"Aung","sequence":"additional","affiliation":[{"name":"Department of Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"},{"name":"Department of Biostatistics, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5973-803X","authenticated-orcid":false,"given":"Matthew D","family":"Cykowski","sequence":"additional","affiliation":[{"name":"Department of Pathology and Genomic Medicine, Houston Methodist Hospital , Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuriko","family":"Katsumata","sequence":"additional","affiliation":[{"name":"Department of Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"},{"name":"Department of Biostatistics, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,13]]},"reference":[{"key":"2024052210164346400_nlae032-B1","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/brain\/awz099","article-title":"Limbic-predominant age-related 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