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 Schwarz, David S Knopman, Bradley F. Boeve, Ronald C. Petersen, Aivi T. Nguyen, R. Ross Reichard, Dennis W Dickson, Clifford R Jr. 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)
JournalAlzheimer's and Dementia
StateAccepted/In press - 2022


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