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

• Published in: Acta neuropathologica Vol. 127; no. 6; pp. 811 - 824
• Main Authors: Josephs, Keith A., Whitwell, Jennifer L., Weigand, Stephen D., Murray, Melissa E., Tosakulwong, Nirubol, Liesinger, Amanda M., Petrucelli, Leonard, Senjem, Matthew L., Knopman, David S., Boeve, Bradley F., Ivnik, Robert J., Smith, Glenn E., Jack, Clifford R., Parisi, Joseph E., Petersen, Ronald C., Dickson, Dennis W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2014; Springer; Springer Nature B.V
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer Disease - psychology; Alzheimer's disease; Apolipoprotein E4 - genetics; Apolipoproteins; Atrophy; Brain - pathology; Brain - physiopathology; Brain research; Cognition & reasoning; Cognition - physiology; Cognitive ability; Dementia; Diagnostic imaging; DNA; DNA-Binding Proteins - metabolism; Female; Health aspects; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Medicine; Medicine & Public Health; Memory; Memory Disorders - genetics; Memory Disorders - pathology; Memory Disorders - physiopathology; Middle Aged; Neuropathology; Neuropsychology; Neurosciences; Original Paper; Pathology; Protein binding; Proteins; Regression Analysis; Sclerosis - pathology; Severity of Illness Index; United States > US; APOE ε4; Braak stage; Alzheimer disease; MRI; TDP-43; Resilience
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-014-1269-z

The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent 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 and 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 ε 4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57 %) cases were TDP-positive. After accounting for age, apolipoprotein ε 4 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.