TDP-43 pathology effect on volume and flortaucipir uptake in Alzheimer's disease

Arenn F. Carlos, Nirubol Tosakulwong, Stephen D. Weigand, Matthew L. Senjem, Christopher G. Schwarz, David S. Knopman, Bradley F. Boeve, Ronald C. Petersen, Aivi T. Nguyen, R. Ross Reichard, Dennis W. Dickson, Clifford R. Jack, Val Lowe, Jennifer L. Whitwell, Keith A. Josephs

Research output: Contribution to journalArticlepeer-review


Introduction: Alzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18F-flortaucipir-positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA-binding protein 43 (TDP-43) was contributing to this volume-uptake mismatch. Methods: Seventy-seven participants with flortaucipir-PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP-43 pathology assessments. Bivariate-response linear regression estimated the effect of age and TDP-43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. Results: Older participants had lower hippocampal volumes and overall flortaucipir uptake. TDP-43-immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP-43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP-43-positives, reflecting the increasing TDP-43 pathology frequency with age. Discussion: TDP-43 pathology is a relevant contributor driving the volume-uptake mismatch in older AD participants. Highlights: TDP-43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP-43 pathology effect is seen in old age due to its increasing frequency. TDP-43 pathology is a relevant driver of the volume-uptake mismatch in old AD patients.

Original languageEnglish (US)
Pages (from-to)2343-2354
Number of pages12
JournalAlzheimer's and Dementia
Issue number6
StatePublished - Jun 2023


  • Alzheimer's disease
  • TDP-43 pathology
  • aging
  • dementia
  • tau-PET
  • volumetric MRI

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health


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