Role of NSAIDs in Alzheimer’s Disease
Inflammatory processes have been implicated in the pathogenesis of Alzheimer’s disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may lessen the inflammatory response by inhibiting cyclooxygenase-1 and cyclooxygenase-2 and by activating the peroxisome proliferator g nuclear transcription factor (PPARα). Results from prior studies examining a protective effect of NSAIDs on the development or progression of Alzheimer’s disease have been inconsistent. Most of these studies have obtained information on NSAID use retrospectively from patients, relatives or medical records. These methods are often incomplete and susceptible to bias, which may lead to misclassification of drug exposure. Pharmacy records in the Netherlands, however, are virtually complete records of drug delivery.
in T’ Veld et al (NEJM 345:1515, 2001) performed a prospective, population-based cohort study to examine the relationship between NSAID use and a decreased risk of Alzheimer’s disease or vascular dementia. The study population was drawn from 10,275 people aged 55 or older living in Ommoord, the Netherlands. Of these 7,983 (78%) agreed to participate. From this group, 6,989 were free from dementia at baseline and did not develop dementia within six months of beginning the study. These patients were screened twice for dementia during the eight-year study period. Study subjects were followed until death, diagnosis of dementia, or end of study.
Complete information on NSAID prescription was obtained from computerized pharmacy records. Dementia was ascertained by using the Mini-Mental State Examination and the Geriatric Mental State Schedule. Patients were then examined by a physician using the Cambridge Mental Disorders of the Elderly Examination diagnostic interview. Subjects believed to have dementia were then examined by a neurologist and a neuropsychologist and underwent magnetic resonance imaging of the brain.
Results: During the study period, 394 subjects were diagnosed with dementia. Of these 293 had Alzheimer’s disease, 56 had vascular dementia and 45 had other types of dementia.
Use of an NSAID at any time, as compared to no use at any time was associated with a lower risk of Alzheimer’s disease (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.09). In those whose cumulative NSAID use was categorized as short-term (1 month or less), the risk of Alzheimer’s disease was 0.95 (95 percent confidence interval, 0.70 to 1.29). Intermediate-term use (1-23 months) was associated with a relative risk of 0.83 (95 percent confidence interval, 0.62 to 1.11) and long-term(>24 months) use of NSAIDs was associated with a relative risk of 0.20 (95 percent confidence interval, 0.05 to 0.83). These reductions in risk could not be attributed to the use of a particular NSAID. No association was found between the use of NSAIDs and the risk of vascular dementia.
Conclusion: The long-term use of NSAIDS may protect against Alzheimer’s disease but not against vascular dementia.
Editorial Comment: This is an important study that may resolve prior conflicting studies on the role of anti-inflammatory drugs in preventing or delaying the onset of Alzheimer’s disease. This study has several important advantages over prior studies. First, it was a prospective study of a large number of patients (>7000) followed over a long period of time (7 years). Second, it utilized pharmacy records to determine NSAID use, a much more accurate method than relying on patient recall of historical NSAID use. A long-term intervention trial of NSAIDs is now indicated and underway in the U.S. through the National Institute of Aging.
