Changes in cognition and amyloid-β processing with long term cholesterol reduction using atorvastatin in aged dogs

M. Paul Murphy, Jacqueline Morales, Tina L. Beckett, Giuseppe Astarita, Daniele Piomelli, Adam Weidner, Christa M. Studzinski, Amy L.S. Dowling, Xiaohong Wang, Harry Levine, Richard J. Kryscio, Yushun Lin, Edward Barrett, Elizabeth Head

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes.

Original languageEnglish
Pages (from-to)135-150
Number of pages16
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - 2010


  • Amyloid-β protein precursor (AβPP)
  • LRP-1
  • canine
  • cholesterol
  • dog
  • statin
  • β-secretase (BACE1)

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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