Pathological drivers of neurodegeneration in suspected non-Alzheimer’s disease pathophysiology

Research output: Contribution to journalArticle


Background: Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects. Methods: Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume. Results: SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. Conclusion: SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported.


  • L. E.M. Wisse
  • R. de Flores
  • L. Xie
  • S. R. Das
  • C. T. McMillan
  • J. Q. Trojanowski
  • M. Grossman
  • E. B. Lee
  • D. Irwin
  • P. A. Yushkevich
  • D. A. Wolk
  • Alzheimer's Disease Neuroimaging Initiative
External organisations
  • University of Pennsylvania
  • University of Caen Normandy
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
  • Neurosciences


  • Hippocampus, Limbic-predominant age-related TDP-43 encephalopathy, Medial temporal lobe, Neurodegeneration, Neurodegenerative pathologies, Neuropathologies diagnosis, Primary age-related tauopathy, Suspected non-Alzheimer’s pathophysiology
Original languageEnglish
Article number100
JournalAlzheimer's Research and Therapy
Publication statusPublished - 2021 Dec
Publication categoryResearch