Oxidative damage is the earliest event in Alzheimer disease

Akihiko Nunomura, George Perry, Gjumrakch Aliev, Keisuke Hirai, Atsushi Takeda, Elizabeth K. Balraj, Paul K. Jones, Hossein Ghanbari, Takafumi Wataya, Shun Shimohama, Shigeru Chiba, Craig S. Atwood, Robert B. Petersen, Mark A. Smith

Research output: Contribution to journalArticlepeer-review

1637 Scopus citations


Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in Aβ deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE ε4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.

Original languageEnglish
Pages (from-to)759-767
Number of pages9
JournalJournal of Neuropathology and Experimental Neurology
Issue number8
StatePublished - 2001


  • 8-hydroxyguanosine
  • Alzheimer disease
  • Amyloid β
  • Apolipoprotein E
  • Neurofibrillary tangle
  • Nitrotyrosine
  • Oxidative stress


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