NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies
Patrick L McGeer1, Edith G McGeer
1Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada. mcgeerpl@interchange.ubc.ca
Abstract:
This review reports correlations between four independent fields related to inflammation and Alzheimer disease: fundamental pathology, epidemiology, transgenic animal studies and clinical trials. Activated microglia, along with a spectrum of inflammatory mediators, have been identified in association with the lesions of Alzheimer disease (AD), suggesting that antiinflammatory agents such as NSAIDs should protect against the disease. In multiple epidemiological investigations testing this hypothesis, a significant risk reduction, or a trend towards such a reduction has been observed in long term as opposed to short term users of traditional NSAIDs. In studies where such NSAIDs have been administered to AD transgenic mice, a dose dependent reduction in pathology was observed. The selective C0X-2 inhibitors were ineffective. Results of clinical investigations have so far been disappointing but have nevertheless correlated with fundamental pathological findings and with transgenic mouse results. Four clinical trials using selective COX-2 inhibitors failed which is in keeping with the animal results and is consistent with pathological findings demonstrating that COX-1 and not COX-2 is the appropriate target in activated human microglia. A low dose trial of the traditional NSAID naproxen also failed, but pilot trials using therapeutically established doses of indomethacin and diclofenac/misoprostol showed promise. Further clinical investigations with relatively high doses of traditional NSAIDs might be warranted, although significant side effects should be anticipated.
Insights
Non-steroidal anti-inflammatory drugs (NSAIDs) show promise in reducing Alzheimer disease (AD) risk, particularly traditional NSAIDs. While COX-2 inhibitors were ineffective, further trials with traditional NSAIDs may be warranted despite potential side effects.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Alzheimer disease (AD) pathogenesis involves inflammation, with activated microglia and inflammatory mediators observed at lesions.
- Non-steroidal anti-inflammatory drugs (NSAIDs) are hypothesized to offer protection against AD.
- Epidemiological studies suggest long-term NSAID use correlates with reduced AD risk.
Purpose of the Study:
- To review correlations between inflammation and AD across pathology, epidemiology, animal models, and clinical trials.
- To evaluate the efficacy of NSAIDs, including selective COX-2 inhibitors, in Alzheimer disease.
- To identify the appropriate molecular targets for anti-inflammatory therapies in AD.
Main Methods:
- Review of epidemiological data on NSAID use and AD risk.
- Analysis of studies involving NSAID administration in transgenic AD mouse models.
- Examination of results from clinical trials of NSAIDs, including selective COX-2 inhibitors, in AD patients.
Main Results:
- Long-term use of traditional NSAIDs showed a risk reduction for AD, unlike short-term use.
- Dose-dependent reduction in AD pathology was observed in transgenic mice treated with NSAIDs.
- Selective COX-2 inhibitors were ineffective in both animal models and clinical trials.
- Clinical trials with selective COX-2 inhibitors failed, aligning with animal and pathological findings indicating COX-1 as the target in human microglia.
- Pilot trials with indomethacin and diclofenac/misoprostol showed promise, while a low-dose naproxen trial failed.
Conclusions:
- COX-1, not COX-2, appears to be the appropriate target for anti-inflammatory treatment in activated human microglia relevant to AD.
- Traditional NSAIDs, particularly at therapeutically established doses, warrant further clinical investigation for AD, with careful consideration of potential side effects.
- Findings suggest a potential therapeutic role for traditional NSAIDs in Alzheimer disease management, supported by converging evidence from multiple research fields.
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