A Pharmacist's Guide to OTC Therapy: NSAIDS and Alzheimer's Risk

Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia.

Dating back to the 1990s, a number of observational studies have investigated whether the use of nonsteroidal antiinflammatory drugs (NSAIDs) can prevent the onset or lower an individual’s risk of developing Alzheimer’s disease (AD).¹ Although the pathogenesis of AD is poorly understood, research indicates that inflammatory mechanisms are involved. ^2,3 Early observational studies suggested that NSAIDs could delay or prevent the onset of AD.³ More recently, some studies have reported a reduction in risk, whereas others have found no association between the two.^1,2,4

The Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) was designed to help address this issue. Study participants were ≥70 years of age with a familial history of Alzheimer’s-like dementia. Prior to the start of the trial, they were required to test “normal” on a battery of cognitive tests.⁵ Participants were randomly given either 200 mg of celecoxib, 220 mg of naproxen sodium twice a day, or a placebo.⁵ AD was the primary outcome measure; secondary outcome measures were cognitive decline and measures related to safety of the treatments with long-term use.⁵

Enrollment began in March 2001 and ended in December 2004, however, when treatments were suspended because of concerns regarding the cardiovascular safety of these agents.⁵ Researchers hoped that the ADAPT study would help clarify any association between NSAID use and AD risk, but because the trial was discontinued prematurely, the early results failed to demonstrate a decrease in AD risk.³

In a study reported in Neurology (May 22, 2007), the efficacy and safety of naproxen and celecoxib for the primary prevention of AD was evaluated. The researchers concluded that the results do not support the hypothesis that celecoxib or naproxen prevent AD, at least within the early years after initiation of treatment. The researchers suggest that long-term follow-up of these participants would be necessary.³

In another study, Szekely et al investigated the association between the use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen and the incidence of dementia and AD.⁶ The results demonstrated that the use of NSAIDs was linked to a reduced risk of AD, but not vascular dementia, and that the study participants who benefited from NSAID use were only those who carried the APOE4 gene, which increases the likelihood of AD.⁶ No effects were found with acetaminophen or aspirin.⁶

According to a study published in the May 6, 2008, issue of Neurology, Vlad et al reported that long-term use of ibuprofen and other drugs commonly used as analgesia to treat mild-to-moderate pain was associated with a lower risk of AD.⁷ In this study, researchers identified 49,349 US veterans aged ≥55 who developed AD and 196,850 veterans without dementia. The study examined >5 years of data and looked at the use of several NSAIDs.⁷ The study found individuals who specifically used ibuprofen for >5 years were >40% less likely to develop AD. Results also showed that the longer ibuprofen was used, the lower the risk for dementia.⁷

A trial by Martin et al evaluating the effects of naproxen sodium and celecoxib on cognitive function in older adults found that the use of naproxen or celecoxib did not improve cognitive function.⁸

Another study by Arvanitakis et al tested the hypothesis that the use of all NSAIDs will lower the risk of AD, decrease AD pathology, and is associated with a slower rate of cognitive decline. The results of this study found no apparent relation of NSAIDs to incidence of, change in cognition, or AD pathology.⁹

According to a study published in Neurology (June 2, 2009), NSAIDs, such as ibuprofen and naproxen, may delay the onset of AD, but do not prevent it.² This study followed 2736 people for 12 years who had an average age of 75 and did not have dementia. At the beginning of the study, 351 patients were heavy users of NSAIDs, and 107 became heavy NSAID users during the follow-up period. Heavy use was defined as having prescriptions for NSAIDs ≥68% of the time over a 2-year period.² Researchers reported that among individuals ≥65 years of age, heavy NSAID users were 66% more likely to develop dementia and 57% more likely to develop AD.²

Conclusion

The National Institute on Aging notes that although some epidemiologic studies suggest an association between a decreased risk of AD and commonly used NSAIDs, clinical trials to date have not demonstrated a benefit for AD from these drugs. Researchers will continue to look for ways to evaluate how anti-inflammatory agents may affect the development or progression of AD.¹⁰ Thus, results of the most recent studies do not offer enough clinical evidence to advocate the use of NSAIDs as preventive agents for AD.⁸ The use of NSAIDs is associated with various drug—drug interactions and contraindications, and long-term use of NSAIDs is associated with various risks and adverse reactions. Key points to make when discussing this issue with patients might include explaining that the National Institute on Aging believes that research findings currently do not support using NSAIDs for prevention of AD or cognitive decline.⁸ Patients with concerns or those with increased risk factors for AD, such as having a family history, should discuss this issue with their primary health care provider.