Clinical Criteria for LATE Distinguish Cognitive Trajectories from Alzheimer Disease

For decades, the clinical diagnosis of dementia in the oldest-old was largely synonymous with Alzheimer disease, yet autopsy studies have frequently revealed a distinct proteinopathy involving the transactive response DNA-binding protein of 43 kDa (TDP-43), a protein typically associated with amyotrophic lateral sclerosis that misfolds and aggregates in the aging brain [1]. This condition, now termed limbic-predominant age-related TDP-43 encephalopathy (LATE), often presents as an amnestic syndrome that is clinically indistinguishable from Alzheimer-type dementia [2, 3]. While Alzheimer disease is defined by amyloid-beta plaques and tau tangles, LATE involves a stereotypical progression of TDP-43 inclusions through the amygdala and hippocampus [1, 4]. In a longitudinal study of 3,606 memory clinic patients, those classified with Probable-LATE demonstrated slower cognitive decline on the Mini-Mental State Examination (p = 0.02) and a lower mortality risk (hazard ratio 0.70; 95% CI, 0.49 to 0.99) compared to those with Alzheimer disease [5]. However, the presence of comorbid LATE and Alzheimer pathology, which occurs in approximately 3.5% of symptomatic clinic patients, significantly accelerates decline in executive functioning (p = 0.03) and increases mortality (hazard ratio 1.25; 95% CI, 1.01 to 1.53) [5, 6, 7]. A recent study now evaluates how well clinical criteria can separate these distinct biological entities to improve longitudinal care and prognostic counseling for symptomatic patients.