A review of Limbic-predominant age-related TDP-43 encephalopathy (LATE)
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently recognized neurodegenerative dementia in the most elderly individuals, characterized by accumulation of TDP-43 protein aggregates in limbic and medial temporal lobe structures. This is clinically important pathology as it often mimics Alzheimer’s disease (AD) and is now understood to be a common contributor to cognitive decline in the “oldest-old”. Pathologically, LATE is distinguished from AD by TDP-43-positive neuronal inclusions (rather than amyloid plaques and neurofibrillary tangles), typically affecting the amygdala, hippocampus, and other limbic regions, often accompanied by hippocampal sclerosis. Clinically, LATE presents with a gradually progressive amnestic dementia syndrome similar to AD which complicates diagnosis. Currently, there are no established antemortem biomarkers for LATE, and definitive diagnosis relies on postmortem confirmation. However, an AD-like dementia with negative amyloid and tau biomarkers in a patient of advanced age is suggestive of LATE. No disease-modifying treatment exists at this time, however multiple therapeutic strategies are under investigation, including immunotherapies targeting pathological TDP-43, small molecules that enhance TDP-43 clearance, and gene or antisense approaches to mitigate TDP-43 toxicity. Continued research is critical to develop effective biomarkers and therapies for this prevalent but under-recognized TDP-43 proteinopathy.