Introduction

Most of us have probably read of the new study that suggests that taking an NSAID (a nonsteroidal anti-inflammatory drug) can protect you from getting Alzheimer's disease. Indeed, many of us in the upper age brackets are wondering if we should start taking something like ibuprophen (Advil) or diclofenac (Voltaren), just in case. Here's a summary of the study and an accompanying editorial¹ published in the New England Journal of Medicine.

As we have pointed out in an earlier article, the pathological process termed inflammation occupies a central position in the development of Alzheimer's disease.² So using an anti-inflammatory drug would appear a logical step. Several studies done in the early 1990s showed that taking NSAIDs was associated with delayed onset or a reduced frequency of Alzheimer's. Since then, however, two other studies were unable to reproduce this effect. Why the differences in results? It seems the timing or duration of NSAID use was probably responsible.

How the study was done

This analysis was done using people enrolled in the Rotterdam Study. All persons over 55 living in a Rotterdam suburb were invited to participate; of 10,000-plus eligible people, almost 8,000 agreed. In the Netherlands full medication records are kept on pharmacy computers. This meant that it was possible to look for a link between taking NSAIDs and the development of Alzheimer's.

After excluding people with existing dementia and those who got lost to follow up, there were almost 7,000 people who were examined extensively at least three times during the eight years, January 1991 to December 1998. They had two screening tests for dementia, examination by a neurologist and neuro-psychologist, and many of them had brain MRIs. Finally a panel decided on the final diagnosis of dementia (which could be Alzheimer's disease or vascular dementia) in those with positive results.

Medications prescriptions allowed the user of NSAIDs and aspirin to be grouped according to duration of treatment: non-use, short-term use (1 month or less), intermediate-term use (1 to - 24 months), and long-term use (24 months or more). (Aspirin was included in the study, as it has anti-inflammatory properties, although it's not counted as a regular NSAID, such as ibuprofen or diclofenac).

The Rotterdam results

The average follow-up period was almost 7 years. Dementia was detected in 394 people, of whom 75% had Alzheimer's disease. The 5 commonest NSAIDs used were diclofenac (Voltaren), ibuprofen (Advil, Motrin), naproxen (Aleve, Anaprox), piroxicam (Feldene), and indomethacin (Indocid), in that order.

Taking an NSAID for any time-period, compared with non-use, showed a slight trend to a reduced risk of developing Alzheimer's during the 7-year period. In NSAID-users the overall likelihood was 86% of that for non-users; this was not a statistically significant finding.

However, the duration of medication with NSAIDs was found to be very important. With less than one month's use and with 1 - 24 months' use, the likelihood of developing Alzheimer's was 95% and 83%, respectively. Again, these findings were not statistically significant. But, for those taking an NSAID for 24 months or longer, the likelihood of developing Alzheimer's was only 20% of that for non-users.

Put another way: the chances of getting Alzheimer's disease in the 8-year period was 8.2% in non-users of NSAIDs, compared with 1.3% in those taking NSAIDs for at least two years.

The risk reduction to 20% seen with 2-year-plus use of NSAIDs could not be attributed to any one particular NSAID. On the other hand, aspirin, when taken for more than 1 month, was associated with an increased risk of vascular dementia, whereas NSAID medication had no effect on the risk of vascular dementia.

While the frequency of Alzheimer's disease obviously increased with age, the 'protective' action of NSAIDs in this study were unaffected by age - it was seen equally in those over 80. The dose of the NSAID was also unimportant, as well as use of steroid medications at the same time, or estrogen-use by women.

So, what to do?

Why should we pay more attention to the results of this study than those from earlier, less conclusive studies? There are several technical reasons. Most important, however, is the fact that the results go a long way towards explaining discrepancies in the earlier results. There seems to be a critical period during which taking NSAIDs may protect against Alzheimer's, that ends about two years before the point where Alzheimer's can be readily detected.

Most physicians are wary about using a possibly toxic drug without an obvious disease to treat. So they are not likely to suggest that all people over 70 should take an NSAID, 'just in case'. Long-term well-controlled trials to prove the value of NSAIDs in preventing or delaying Alzheimer disease are running, but they will take several years to complete. Should those of us over 70 wait this long? The chance of developing Alzheimer disease increases dramatically after age 75, and one needs 2 years of NSAID treatment to have a chance of protection, as this study has shown.

Obviously, the choice is one to be made on an individual basis, between you and your physician. The risks of NSAID medication are known - they usually involve stomach irritation and possible bleeding. Individual medical histories will affect the decision, too. But, at 71, this author will seriously consider starting on a low daily dose of ibuprofen in the next year or so . . . . . .unless new results in the meantime point out that this is not such a good idea!

Note: A large well-controlled study just published in the Journal of the American medical Association has shown that treating mild-to-moderate Alzheimer's patients with naproxen or rofecoxib (a COX-2 inhibitor) was not effective in slowing progression of the disease. Side effects were more common in the people taking the anti-inflammatory drugs than in the placebo controls. This result is not inconsistent with the above study, where the NSAIDs were shown to have a preventative effect rather than a treatment effect; however, they deserve consideration when thinking of taking an NSAID to prevent dementia. Robert Griffith.