Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE): A Structured Literature Search and Narrative Review of Neuropathological, Clinical, Genetic, and Biomarker Evidence

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a TDP-43 proteinopathy predominantly affecting limbic structures in older adults. This narrative review synthesizes evidence on neuropathology, clinical phenotypes, diagnostic frameworks, genetics, neuroimaging, and fluid biomarkers, distinguishing neuropathologically confirmed LATE neuropathologic change (LATE-NC) from probabilistic clinical LATE. A structured literature search centered on PubMed/MEDLINE and covering publications through 4 August 2026, was supplemented by OpenAlex, Europe PMC, citation tracking, and targeted registry searches. Historical HS-Aging and cerebral age-related TDP-43 with sclerosis (CARTS) terminology was also considered. Primary human studies were prioritized; no new meta-analysis was performed. LATE-NC is frequent in advanced age, although its prevalence varies across autopsy cohorts; it commonly coexists with Alzheimer disease neuropathologic change (ADNC). The limbic-predominant amnestic neurodegenerative syndrome (LANS) describes a clinical syndrome rather than TDP-43 pathology. Prospective autopsy-based diagnostic-accuracy validation of the 2025 clinical LATE criteria remains unavailable. Genetic associations are most consistently supported for apolipoprotein E (APOE), transmembrane protein 106B (TMEM106B), and granulin precursor (GRN). MRI and FDG-PET can support the assessment of limbic neurodegeneration but do not directly detect TDP-43. Candidate TDP-43 PET tracers, plasma TDP-43, cryptic-exon biomarkers, and cerebrospinal fluid (CSF) seed-amplification assays remain investigational. No clinically validated molecularly specific biomarker is available for LATE-NC. Priorities are prospective validation of clinical criteria and development of LATE-specific molecular biomarkers.