Molecular signatures and biomarker development for limbic-predominant age-related TDP-43 encephalopathy (LATE)

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative disease marked by TDP-43 proteinopathy, affecting approximately one-third of individuals aged 80 and above. 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 pattern of LATE-NC differs from that seen in frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP).  LATE-NC can occur in a "pure" form but more commonly exists alongside other dementia-related comorbidities, including both degenerative and vascular pathologies. When those "mixed" pathologies are factored in, LATE contributes significantly to cognitive decline in human populations.  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's 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.