NSAIDs Protect Against Alzheimer’s Disease
March 15, 2002
NSAIDs Protect Against Alzheimer’s Disease
Abstract & Commentary
Synopsis: Long-term use of NSAIDs decreased the risk of developing Alzheimer’s disease in a prospective study with 7 years average follow-up, but there was no protection against developing other vascular dementias.
Sources: in t’ Veld BA, et al. N Engl J Med. 2001;345:1515-1521; Breitner JC, et al. N Engl J Med. 2001;345:1567-1568.
As part of an ongoing population study in the Netherlands, all individuals born in 1912 or earlier living in a certain district were invited to participate in this research, and 1810 enrolled (78% of eligible residents). Women made up 78% of the sample, and 13% resided in institutions. Absence of initial dementia was established with both the Mini-Mental Status Exam (MMSE) and clinical confirmation when the study began in 1987-1989, with reassessment on all participants every 3 years. Drug data were collected from pharmacy data 1991-1998, and further confirmed during the follow-up 1994-1996 through interviews and collection of the actual drug containers.
Since nearly 100% of the participants used 1 of 7 computerized pharmacies in their district, accurate data on drug use were obtained over a 7-year period. For the majority of the study period, nonsteroidal anti-inflammatory drugs (NSAIDs) could only be obtained by prescription from these pharmacies. For comparison of dosages, an average dose was established based on use for the main indication, for example, diclofenac 100 mg/d (43% of total prescriptions), ibuprofen 1200 mg/d (22% of total), and naproxen 500 mg/d (18% of total). The yearly rate of use varied minimally over time, between 37-40 days per 1000 person days over 8 years of follow-up. The most common reasons for NSAID use were joint symptoms (50%), osteoarthritis (24%), and rheumatoid arthritis (3%).
Decreasing risk of Alzheimer’s disease was found with increasing cumulative duration of NSAID use, which reached statistical significance after 24 months of cumulative use. The relative risk of developing Alzheimer’s disease was 0.20, compared to 0.83 with 1-23 months of cumulative NSAID use, and 0.95 with less than 1 month of use. Oral salicylates, such as aspirin and other platelet-inhibiting salicylates pharmacologically related to NSAIDS, were also tracked, but no risk reduction for Alzheimer’s Disease was found.
In this cohort which involved nearly 50,000 person-years of follow-up, 394 patients developed dementia, of which 293 were Alzheimer’s, 56 vascular dementia, and 45 other types. These diagnoses were established according to DSM III criteria by both a neurologist, neuropsychologist, and MRI brain scan. Other variables were also investigated, but no associations in the development of Alzheimer’s were found with age, use of estrogens, corticosteroids or other non-narcotic analgesics, or with presence of apolipoprotein E alleles. The risk reduction for Alzheimer’s disease was present after 24 months of cumulative use regardless of the daily dose used or the specific NSAID used. No risk reduction for the other types of dementia was found in association with any of the variables analyzed.
Comment by Mary Elina Ferris, MD
Since brain pathology of Alzheimer’s disease includes indications of an inflammatory response, there has been speculation that drugs such as NSAIDs that inhibit this response may be able to reduce the associated neurological damage. Previous observational studies such as the Baltimore Longitudinal Study of Aging1 have suggested such a protective effect after 2 years of NSAID use, but they were limited by self-reported and retrospective drug information. This study presents much more accurate pharmacy information in a prospective analysis, and appears to confirm a very significant effect of long-term NSAID use on diminished development of Alzheimer’s disease.
In an accompanying editorial, Breitner and colleagues from Johns Hopkins University credit this article as important to resolving previous contradictory results about NSAIDs and Alzheimer’s disease. Current concepts now include the onset of a process in midlife or earlier that initiates a cascade of events marked by accumulation of amyloid plaques and neurofibrillary tangles that leads to a loss of synapses in the hippocampus and cerebral cortex, with inflammatory mechanisms proposed as important mediators in the pathogenetic cascade.
There is now thought to be a critical period that ends about 2 years before the development of dementia during which exposure to NSAIDs at any dose may protect against Alzheimer’s disease. This explains why previous short-term studies did not show the protective effect, and why treatment with NSAIDs after the development of symptoms in the prodromal phase or after diagnosis of Alzheimer’s disease has not been shown to be helpful.
Even though this study did not show aspirin use to also give this protective effect, other studies have shown a reduction in the development of Alzheimer’s disease, although not as great as with NSAIDs.2 The new Netherlands study was not able to track nonprescription use of aspirin as well as NSAIDs, so it should not be ruled out as a possibility. The next step in clearly establishing the usefulness of NSAIDs to prevent Alzheimer’s disease will be in randomized controlled trials, which are currently being funded by the National Institute on Aging comparing naproxen and celecoxib. In the meantime, clinicians have yet another reason to promote NSAID use in the middle aged and older population.
Dr. Ferris, Clinical Associate Professor, University of Southern California, is Associate Editor of Internal Medicine Alert.
References
1. Stewart WE, et al. Neurology. 1997;48:626-632.
2. Broe GA, et al. Arch Neurol. 2000;57:1586-1591.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content