NSAIDs Don't Prevent Alzheimer's Disease

May 5, 2009

For a long time, many have held the strong opinion that non-steroidal anti-inflammatory drugs might prevent Alzheimer's Disease.

For a long time, many have held the strong opinion that non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and ibuprofen might prevent Alzheimer's Disease (AD). The evidence for this is a bit mixed, but several well conducted population studies find a lower incidence of AD in prior NSAID users. As a result, some practitioners recommended taking such drugs as prophylaxis. So, what do we tell our patients to do to reduce AD risk?

The American Academy of Neurology published an evidence-based guideline in 2001 (which it affirmed in 2003) on treatment of AD. On NSAIDs: "The use of anti-inflammatory agents, prednisone, and estrogen to prevent the progression of AD are not supported by prospective data." The associated specific treatment recommendation is: "There is insufficient evidence to support the use of other antioxidants, anti-inflammatories, or other putative disease-modifying agents specifically to treat AD because of the risk of significant side effects in the absence of demonstrated benefits." At least based on this guideline, recommending NSAIDs for dementia prophylaxis is not a good idea.

And, more evidence supporting this position is now available. Recently, a study (e-publication ahead of print) was published online in Neurology reflecting a strongly increased risk of AD in older persons taking NSAIDs. The authors, a University of Washington group, studied community dwelling older (> 64 y.o., with mean age 74.8) persons who were participating in a large ongoing long term dementia study. This is a prospective database with careful follow up and a large cohort. A subgroup of 2,736 patients was analyzed for this study. Pharmacy records were available dating back to 1977: Of note is the availability of strength and amount dispensed for each drug, in addition to drug name. Exposure data were derived from both pharmacy records and self-reporting, and patients were then stratified into 3 NSAID exposure level groups (light, medium and heavy). Both all-cause dementia and AD were evaluated.

The results are quite interesting. Ibuprofen was by far the most commonly used agent. This, together with naproxen, indomethacin and sulindac (in order of decreasing frequency) accounted for >80% of drug exposures. The analysis is rather complex, using several different statistical models. In the primary model, the relative risk for heavy NSAID users for all-cause dementia was 1.66 (1.24-2.24). The risk for dementia was considerably higher with recent users of NSAIDs compared to distant users. The authors controlled for a large number of factors and did a variety of germane sensitivity analyses. Their results appear to be quite rigorously derived. And a risk increase of 2/3 is large and quite clinically significant.

This study contradicts the findings of many previous studies, showing a clear increase in incidence of AD in people using NSAIDs. The differences in outcomes may be due to a longer and more stringent evaluation of prior NSAID use in the current study, or a variety of other factors. However, the authors think the difference in result is due to the older age of the cohort in this study. An accompanying editorial comments on the factor of timing of exposure, e.g. much younger persons may show a beneficial effect whereas older patients show a higher AD risk.

Complexities notwithstanding, the findings are clear: In this group of people 65 years old or older, NSAIDs increased the risk of AD (and other dementias) by a large margin. In light of these findings, it is clear that a prescriber cannot recommend NSAIDs to prevent dementia in patients over 65 years old. Recommendations for younger patients are not so clear. Watch this space.