A review of Limbic-predominant age-related TDP-43 encephalopathy (LATE)
TL;DR
Clinically, LATE presents with a gradually progressive amnestic dementia syndrome similar to AD which complicates diagnosis, and definitive diagnosis relies on postmortem confirmation, so continued research is critical to develop effective biomarkers and therapies for this prevalent but under-recognized TDP-43 proteinopathy.
Abstract
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.