TDP-43 is a key player in the clinical features associated with Alzheimer’s disease

Abstract

The aim of this study was to determine whether the TAR DNA-binding protein of 43kDa (TDP-43) independently has any effect on the clinical and neuroimaging features typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. Additionally, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred ninety-five (57%) cases were TDP-positive. After accounting for age, apolipoprotein ε4, and other pathologies, TDP-43 had a strong effect on cognition, memory loss, and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.

The TDP‐43 N‐terminal domain structure at high resolution

“…5D) and previously by Qin et al [22]. Importantly, we found that both the DNA oligos (TT) 6 and (TG) 6 …”

“…Nine years ago, TDP-43 was found to form aberrant polyubiquitinated, hyperphosphorylated cytosolic aggregates that have been causatively linked to amyotrophic lateral sclerosis/ frontotemporal lobar degeneration (ALS/FTLD) [4,5] and, more recently, to Alzheimer's disease [6]. The protein contains an N-terminal domain (NTD), two RNA recognition motif (RRM) RNA-binding domains and a long, intrinsically disordered C-terminal region.…”

Hippocampal Sclerosis and Epilepsy in Elderly Population

“…Noteworthy, TDP43-pathology has been reported to be relatively common in AD [4][5][6][7][8][9][10][11][12][13][14] and in line with this, TDP43-pathology was observed in as many as 88% of our cases with severe AD related pathology (Braak stages V-VI). It should be noted that clinical studies reporting that EP is common in AD include all subjects with AD diagnosis.…”

“…In AD, the hippocampal formation displays substantial pathology including AD related hallmark lesions such as neurofibrillary tangles and neuritic plaques [3]. Furthermore, many reports have indicated that a substantial number of AD subjects, in addition to the AD related lesions, also display TAR DNA binding protein 43 (TDP43) within the hippocampus [4][5][6][7][8][9][10][11][12][13][14]. TDP43 related pathology is primarily seen in subjects with frontotemporal lobar degeneration (FTLD) [15].…”

Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers

“…Additional data are required to further characterize the existing tau radioligands, including quantitative validation toward full kinetic modeling, test-retest studies, and human dosimetry. Ultimately, neuropathologic correlations with PET imaging findings will be necessary to confirm tau selectivity against colocalized key proteins besides Ab, such as a-synuclein and TDP-43 (21). Head-to-head studies will allow direct comparisons between radiotracers.…”