Neurodegenerative changes in early-and late-onset cognitive impairment with and without brain amyloidosis

Eddie C. Stage, Diana Svaldi, Meredith Phillips, Victor Hugo Canela, Tugce Duran, Naira Goukasian, Shannon L. Risacher, Andrew J. Saykin, Liana G. Apostolova

Research output: Contribution to journalArticle


Background: A substantial number of patients clinically diagnosed with Alzheimer's disease do not harbor amyloid pathology. We analyzed the presence and extent of tau deposition and neurodegeneration in amyloid-positive (AD) and amyloid-negative (nonAD) ADNI subjects while also taking into account age of onset (< or > 65 years) as we expected that the emerging patterns could vary by age and presence or absence of brain amyloidosis. Methods: One hundred and ten early-onset AD (EOAD), 121 EOnonAD, 364 late-onset AD (LOAD), and 175 LOnonAD mild cognitive impairment (MCI) and dementia (DEM) subjects were compared to 291 ADNI amyloid-negative control subjects using voxel-wise regression in SPM12 with cluster-level family-wise error correction at p FWE < 0.05). A subset of these subjects also received 18F-flortaucipir scans and allowed for analysis of global tau burden. Results: As expected, relative to LOAD, EOAD subjects showed more extensive neurodegeneration and tau deposition in AD-relevant regions. EOnonADMCI showed no significant neurodegeneration, while EOnonADDEM showed bilateral medial and lateral temporal, and temporoparietal hypometabolism. LOnonADMCI and LOnonADDEM showed diffuse brain atrophy and a fronto-Temporo-parietal hypometabolic pattern. LOnonAD and EOnonAD subjects failed to show significant tau binding. Conclusions: LOnonAD subjects show a fronto-Temporal neurodegenerative pattern in the absence of tau binding, which may represent underlying hippocampal sclerosis with TDP-43, also known as limbic-predominant age-related TDP-43 encephalopathy (LATE). The hypometabolic pattern observed in EOnonADDEM seems similar to the one observed in EOADMCI. Further investigation into the underlying etiology of EOnonAD is warranted.

Original languageEnglish (US)
Article number93
JournalAlzheimer's Research and Therapy
Issue number1
StatePublished - Aug 5 2020


  • AD
  • Alzheimer's disease
  • Early onset
  • Hippocampal sclerosis
  • LATE
  • Late onset
  • Limbic-predominant age-related TDP-43 encephalopathy
  • MRI
  • Neurodegeneration
  • PET
  • Tau

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

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