TDP-43 proteinopathy: the complex biological and clinical findings in LATE-NC, LANS, and other mixed age-related major neurocognitive disorders.

Since the term limbic-predominant age-related TDP-43 encephalopathy (LATE) was coined in 2019, more than 200 articles addressing the subject were published. This review aims to provide an updated synthesis of knowledge regarding LATE-NC as a cause of age-related neurodegeneration and cognitive decline while addressing the challenges posed by overlapping neuropathologies in aging populations. LATE-NC is marked by TDP-43 deposition in limbic structures, such as the amygdala and hippocampus, and is often associated with cognitive decline resembling Alzheimer's disease, though with a slower progression in isolated cases. The frequent coexistence of LATE-NC with other neuropathologies, particularly Alzheimer's disease neuropathologic changes (ADNC) and Lewy body dementia (LBD), exacerbates dementia severity and complicates diagnosis and treatment. Recent efforts have established clinical criteria for in-vivo diagnosis, including neuroimaging markers like hippocampal atrophy and limbic hypometabolism. Genetic studies have identified key risk genes, including GRN, TMEM106B, SORL1, and APOE, while biomarker development in cerebrospinal fluid (CSF) and blood remains in its early stages. The review underscores the need for multidisciplinary research and clinical approaches to address the complexities of neurodegenerative diseases involving TDP-43 proteinopathy, improve diagnostic accuracy, and develop effective treatments tailored to individual patient profiles.