TDP-43: From Alzheimer’s Disease to Limbic-Predominant Age-Related TDP-43 Encephalopathy

Abstract

Since the discovery of TAR DNA-binding protein 43 (TDP-43) in 1995, our understanding of its role continues to expand as research progresses. In particular, its role in the pathogenesis of Alzheimer's disease (AD) has drawn increasing interest in recent years. TDP-43 may participate in various pathogenic mechanisms underlying AD, such as amyloid β deposition, tau hyperphosphorylation, mitochondrial dysfunction, and neuroinflammation. Because AD is complex and heterogeneous, and because of the distinct characteristics of TDP-43, mostly seen in the oldest-old and those with more severe clinical phenotype, subcategorization based on specific features or biomarkers may significantly improve diagnosis and treatment. AD-like cognitive dysfunction associated with TDP-43 pathology may therefore be a distinct encephalopathy, referred to as limbic-predominant age-related TDP-43 encephalopathy (LATE).

The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies

“…α-Synuclein is the major component protein of pathological deposits in PD 6 , 7 . Furthermore, TAR DNA-binding protein 43 (TDP-43) aggregates are frequently observed in multiple diseases, such ALS, FTD, AD, and LATE 8 – 10 .…”

Significance of Blood and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: Sensitivity, Specificity and Potential for Clinical Use

“…An extensive study [ 302 ] was able to link the presence of TDP-43 in AD brains with the likelihood of clinical AD presentation; but to date, a reliable CSF or blood marker is not available, although notable attempts and data are present for ALS [ 303 , 304 ]. Part of the issue is the non-specificity of TDP-43 accumulation, as the concept of a spectrum of TDP-43 neurodegenerative presentation is becoming more evident [ 305 ]. In this context, TDP-43 may be useful as a biomarker in the future to predict course of disease or variants of AD presentation.…”

Biomarkers: Our Path Towards a Cure for Alzheimer Disease

“…166 Furthermore, TDP-43 pathology contributes to inflammation, mitochondrial dysfunction, and neuronal/synaptic injury in AD, and interacts with Aβ and tau pathologies. 166,167 Recent studies suggest the presence of distinct molecular patterns of TDP-43 pathology in AD, including differences in phosphorylation patterns and the prevalence of truncated species, which influence the clinical phenotype and the prevalence of behavioral symptoms. 168 Higher plasma TDP-43 levels in AD, 169 and higher serum levels of TDP-43 related variants in individuals with pre-MCI who later progressed to AD dementia, 170 have been reported.…”

“… 164 , 165 In AD, TDP-43 pathology is predominantly found in limbic structures such as the hippocampus and amygdala, and colocalizes with severe neuronal loss. 166 Several studies report associations between TDP-43 pathology and higher rates of brain atrophy and cognitive impairment in AD. 166 Furthermore, TDP-43 pathology contributes to inflammation, mitochondrial dysfunction, and neuronal/synaptic injury in AD, and interacts with Aβ and tau pathologies.…”

“… 166 Several studies report associations between TDP-43 pathology and higher rates of brain atrophy and cognitive impairment in AD. 166 Furthermore, TDP-43 pathology contributes to inflammation, mitochondrial dysfunction, and neuronal/synaptic injury in AD, and interacts with Aβ and tau pathologies. 166 , 167 Recent studies suggest the presence of distinct molecular patterns of TDP-43 pathology in AD, including differences in phosphorylation patterns and the prevalence of truncated species, which influence the clinical phenotype and the prevalence of behavioral symptoms.…”