Basic Science and Pathogenesis.

Area of Science:

• Neuropathology
• Neurodegenerative Diseases
• Aging Research

Background:

• Recent clinical criteria for limbic-predominant age-related TDP-43 encephalopathy (LATE) were established for in-life diagnosis using clinical assessments and biomarkers.
• This study aimed to assess the utility of these criteria in identifying LATE neuropathologic change (NC) at autopsy.

Purpose of the Study:

• To evaluate the effectiveness of clinical criteria for diagnosing LATE using neuropathological proxies at autopsy.
• To determine the prevalence of LATE-NC in a large cohort using operationalized clinical criteria.

Main Methods:

• Utilized National Alzheimer's Coordinating Center (NACC) data, including last visit assessments and autopsy neuropathology.
• Operationalized LATE criteria using autopsy-derived proxies for biomarkers (hippocampal atrophy, amyloid-beta, tau) and clinical features (progressive amnestic syndrome).
• Analyzed data from 2438 participants, comparing rates of LATE-NC across different LATE classifications.

Main Results:

• 33.4% of participants exhibited LATE-NC. Progressive amnestic syndrome was identified in 45.7% of cases.
• Few participants met criteria for Probable (41.9% LATE-NC) or Possible LATE (50% LATE-NC).
• Higher rates of LATE-NC were observed in Possible LATE with Alzheimer's Disease (AD) compared to unclassified progressive amnestic syndrome (p < 0.001).

Conclusions:

• The operationalized clinical criteria for LATE, using neuropathological proxies, identified Probable and Possible LATE rarely in the NACC cohort.
• LATE-NC rates were similar across all defined LATE groups, suggesting potential limitations in current clinical criteria for autopsy validation.
• Findings highlight the need for further refinement of LATE diagnostic criteria, particularly in diverse populations, given the study's limitations in racial, ethnic, and socioeconomic diversity.