Cognitive and Clinical Characteristics of Patients With Limbic-Predominant Age-Related TDP-43 Encephalopathy

Abstract

Background and objectives: Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects similar neuroanatomical networks as Alzheimer disease (AD) and is often comorbid with AD, though frequently missed in clinical diagnosis. The primary aim of this study was to elucidate the clinical and cognitive differences at baseline between patients with autopsy-confirmed LATE and patients with AD and comorbid LATE + AD.

Methods: Clinical and neuropathologic datasets were requested from the National Alzheimer Coordination Center. Baseline data from individuals older than 75 years during death without neuropathologic indication of frontotemporal lobar degeneration were included in analyses. Pathologically defined groups reflecting LATE, AD, and comorbid LATE + AD were identified. Group differences in clinical characteristics and cognition were explored through analysis of variance and the χ² using measures from the Uniform Data Set measures.

Results: Pathology groups included 31 individuals with LATE (mean age: 80.6 ± 5.4 years), 393 with AD (mean age: 77.8 ± 6.4 years), and 262 with LATE + AD (mean age: 77.8 ± 6.6 years) without significant differences in sex, education, or race. Compared with participants with AD and LATE + AD pathology, participants with LATE pathology lived significantly longer (mean visits: LATE = 7.3 ± 3.7; AD = 5.8 ± 3.0; and LATE + AD = 5.8 ± 3.0; F(2,683) = 3.7, p < 0.05), reported later onset of cognitive decline (mean onset: LATE = 78.8 ± 5.7; AD = 72.5 ± 7.0; and LATE + AD = 72.9 ± 7.0; F(2,516) = 6.2, p < 0.01), and were more likely to be diagnosed as cognitively normal at baseline (LATE = 41.9%; AD = 25.4%; and LATE + AD = 12%; χ² = 38.7, p < 0.001). Individuals with LATE (45.2%) also reported fewer memory complaints than those with AD (74.4%) or LATE + AD (66.4%; χ² = 13.3, p = 0.001) and were less likely to be classified as impaired on the Mini-Mental State Examination (LATE = 6.5%; AD = 24.2%; and LATE + AD = 40.1%; χ² = 29.20, p < 0.001). Across all neuropsychological measures, participants with LATE + AD pathology performed significantly worse than the AD and LATE groups.

Discussion: Those with LATE pathology were older when cognitive symptoms began and lived longer than participants with AD or LATE + AD pathology. Participants with LATE pathology were also more likely to be classified as "cognitively normal" based on objective screening and self-report measures, and they had higher scores on neuropsychological testing. Consistent with prior literature, comorbid pathologies led to more significant cognitive and functional impairment. Early disease characteristics based on clinical presentation alone were insufficient for differentiating LATE from AD, reiterating the need for a validated biomarker.