Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment

Mark A. Smith, Xiongwei Zhu, Massimo Tabaton, Gang Liu, Daniel W. McKeel, Mark L. Cohen, Xinglong Wang, Sandra L. Siedlak, Barney E. Dwyer, Takaaki Hayashi, Masao Nakamura, Akihiko Nunomura, George Perry

Research output: Contribution to journalArticlepeer-review

289 Scopus citations


It is now established that oxidative stress is one of the earliest, if not the earliest, change that occurs in the pathogenesis of Alzheimer's disease (AD). Consistent with this, mild cognitive impairment (MCI), the clinical precursor of AD, is also characterized by elevations in oxidative stress. Since such stress does not operate in vacuo, in this study we sought to determine whether redox-active iron, a potent source of free radicals, was elevated in MCI and preclinical AD as compared to cognitively-intact age-matched control patients. Increased iron was found at the highest levels both in the cortex and cerebellum from the pre-clinical AD/MCI cases. Interestingly, glial accumulations of redox-active iron in the cerebellum were also evident in preclinical AD patients and tended to increase as patients became progressively cognitively impaired. Our findings suggests that an imbalance in iron homeostasis is a precursor to the neurodegenerative processes leading to AD and that iron imbalance is not necessarily unique to affected regions. In fact, an understanding of iron deposition in other regions of the brain may provide insights into neuroprotective strategies. Iron deposition at the preclinical stage of AD may be useful as a diagnostic tool, using iron imaging methods, as well as a potential therapeutic target, through metal ion chelators.

Original languageEnglish (US)
Pages (from-to)353-372
Number of pages20
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - 2010
Externally publishedYes


  • Alzheimer's disease
  • Chelator
  • Diagnostic
  • Free radicals
  • Iron
  • Mild cognitive impairment (MCI)
  • Oxidative stress
  • Pre-clinical
  • Redox activity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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