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LATE neuropathological change (LATE-NC) is characterized by the accumulation of phosphorylated TDP-43 preferentially in the limbic system, with potential extension to the neocortex and other brain regions. Notably, the anatomic\u00a0pattern of LATE-NC\u00a0differs from that seen in frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions\u00a0(FTLD-TDP).\u00a0\u00a0LATE-NC can occur in a \u201cpure\u201d form but more commonly exists alongside other dementia-related\u00a0comorbidities, including both degenerative and vascular pathologies. When those \u201cmixed\u201d pathologies are factored in,\u00a0LATE contributes significantly to cognitive decline in human populations.\u00a0 However, LATE currently lacks a molecular-specific diagnostic method for definitive diagnosis in living people. There are new consensus-based guidelines for predicting the presence of either pure LATE-NC or LATE-NC combined with Alzheimer\u2019s disease neuropathologic change (ADNC). Aimed at developing more specific diagnostic methods, recent research efforts have been directed toward identifying unique features on neuroimaging and molecular signatures in biological fluids such as blood and cerebrospinal fluid to facilitate clinical diagnosis for LATE. This review discusses current progress in molecular understanding of LATE-NC, the search for biomarkers for LATE, and highlights key gaps that need to be addressed to advance early detection and improve patient management and clinical trial stratification.<\/jats:p>","DOI":"10.1007\/s00401-026-03027-0","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:23:04Z","timestamp":1778865784000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular signatures and biomarker development for limbic-predominant age-related TDP-43 encephalopathy (LATE)"],"prefix":"10.1007","volume":"151","author":[{"given":"Ling","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobilola","family":"Akingbade","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter T.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Hsiu J.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"3027_CR1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12939","volume":"31","author":"S Agrawal","year":"2021","unstructured":"Agrawal S, Yu L, Kapasi A, James BD, Arfanakis K, Barnes LL et al (2021) Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and microvascular pathologies in community-dwelling older persons. 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