Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease.
Alzheimer's disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDs). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDs cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD subjects have failed, and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.
Cole
Greg M
GM
Geriatric Research and Education Center, North Hills, CA 91343, USA.
Frautschy
Sally A
SA
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D053327:Apolipoprotein E4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002986:Clinical Trials as Topic; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D053327:Apolipoprotein E4; D052246:Cyclooxygenase 2 Inhibitors; D018696:Neuroprotective Agents