title: 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 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 ε4 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 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.
authors.affiliation: Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, 55905, USA, josephs.keith@mayo.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whitwell
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Nirubol
authors.initials: N
authors.lastname: Tosakulwong
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Liesinger
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Senjem
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ivnik
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Smith
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D053327:Apolipoprotein E4 / Q000235:genetics; D001284:Atrophy; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D003071:Cognition / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D012044:Regression Analysis; D012598:Sclerosis / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D053327:Apolipoprotein E4; D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human