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

Purpose of review: 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.

Recent findings: 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.

Summary: 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.