LATE and AD: Clinical Interactions

LATE and AD: Clinical Interactions

       Most neurological disorders are associated with a biomarker, a protein or biological by-product whose concentration correlates to the development of the disorder. AD’s biomarkers, as you may already know, are amyloid-beta (Aꞵ) precipitated as plaques and misfolded tau protein that forms neurofibrillary tangles (NFTs). Another common biomarker of neurological disorders is TAR DNA binding protein 43 (TDP-43, shown above) which presents in cases of Frontotemporal dementia (FTD), Hippocampal Sclerosis (HS), and Limbic-Predominant TDP-43 Encephalopathy (LATE). But neuropathology is rarely cut and dry which raises the question, “What happens when these biomarkers/disorders occur together?”.

       Recently, researchers answered this question using retrospective analyses on 1,356 elderly participants who were diagnosed at autopsy with either AD, LATE, or AD & LATE (along with cognitively normal participants for control). The researchers used results of cognitive testing over their lifetimes to complete between-group comparisons of cognitive trajectories for global cognition and 5 specific domains (episodic, semantic, and working memory, perceptual speed, and visuospatial processing).

       The results suggest that LATE and AD interact to produce a differential cognitive trajectory. Patients with pure-AD and LATE/AD experience increased decline in global cognition and all sub-domains in comparison to healthy controls. Patients with pure-LATE have increased decline in global cognition, but in sub-domains, only had accelerated decline in episodic memory compared to healthy controls. In comparison to those with pure-AD, those with LATE decline slower in global cognition and episodic memory, while those with LATE/AD decline faster in global cognition and all domains.

       The increased rate of cognitive decline in the AD/LATE group suggests these two disorders appear to have additive effects that produce a specific, accelerated cognitive trajectory. While this may not seem significant, it does support the concept that differential progressions of AD (as well as other neurodegenerative disorders) may be due to interactions with comorbid disorders, such as LATE. This allows for better diagnostics and treatments because, without information about additive effects, physicians may see a patient with AD/LATE and determine that it is a more severe case of AD. Using cognitive trajectories for sub-groups such as AD/LATE, however, they could gain a head-start in diagnosing and treating both disorders.

       Unfortunately, a diagnostic method like this will require a significant amount of research to properly establish due to the amount of people required to create a generalizable cognitive trajectory. Using retrospective analyses, like they did here, saves quite a bit of time but is limited by the outcome measures used in the original study. As such, we will have to make a concerted effort to develop these trends for the numerous neuropathological groups that exist.

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Source:
           Kapasi, A., Yu, L., & Boyle, P. Limbic pre-dominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/14/e1951.long