LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy.

Objective: Although Alzheimer disease (AD) is the most common neurodegenerative cause of dementia, neurologists must be aware of other etiologies that can mimic the amnestic-predominant syndrome and medial temporal brain involvement typically associated with AD. This article reviews recent updates surrounding limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE), hippocampal sclerosis, and primary age-related tauopathy.

Latest developments: LATE neuropathologic change occurs in approximately 40% of autopsied older adults, including occurrences in isolation in some older individuals with amnestic cognitive impairment. LATE neuropathologic change is often, but not always, associated with hippocampal sclerosis (neuronal loss and gliosis in the hippocampus and associated structures) and frequently coexists with AD and other neurodegenerative pathologies. Although there is no direct clinical biomarker for TDP-43 pathology, recent studies suggest that a clinical diagnosis of LATE can be achieved through the integration of multiple data points. Primary age-related tauopathy refers to the pathologic finding (in some cognitively unimpaired older adults as well as some individuals with cognitive impairment) of medial temporal-predominant neurofibrillary tangles in the absence of amyloid-β (Aβ) plaques. Recent consensus frameworks have attempted to resolve ambiguities of nomenclature and diagnosis for these entities, and efforts toward in vivo biomarkers are ongoing.

Essential points: LATE, with or without hippocampal sclerosis, and primary age-related tauopathy belong in the differential diagnosis (along with AD, argyrophilic grain disease, and other disorders) for slowly progressive amnestic-predominant cognitive impairment, particularly in individuals older than 75 years. Accurate recognition of clinical and diagnostic test features supportive of these non-AD entities is vital to optimize patient counseling, therapeutic selection, and novel biomarker development.