We found that long-term users of NSAIDs were at lower-than-expected risk of AD. Our results generally agree with and extend those of prior epidemiologic studies. We found that the protective effect did not seem to be identical for each NSAID: some showed clear protective effects, others did not, and in yet others the effect on AD risk was unclear.
Ibuprofen showed a strong protective effect that increased with duration of use, consistent with nonclinical studies of this Aβ1-42-suppressing NSAID. We were probably able to observe this effect because of the large numbers of users of this medication in the VA system. At least one other Aβ1-42-suppressing NSAID seemed to show a similar effect (indomethacin). However, a number of non–Aβ1-42 suppressors did not show any protective effect (celecoxib, the salicylates). This was also consistent with prior nonclinical studies. Unfortunately, the effect of many NSAIDs was not clear. In particular, small numbers of users made it difficult to ascertain whether other Aβ1-42-suppressing NSAIDs (sulindac, flurbiprofen) showed the same protective effect as ibuprofen. Likewise, it was difficult to confirm that other non-Aβ1-42-suppressing NSAIDs showed no effect.
Attempting to clarify the specific effect of Aβ1-42 suppression, we grouped these drugs together and compared them with non–Aβ1-42-suppressing NSAIDs. There was a duration-dependent protective effect in the former group with CIs that consistently excluded the null with use over 1 year. The curve was similar to that for ibuprofen alone, suggesting that this NSAID may have been responsible for most of the protective effect observed. However, the non–Aβ1-42-suppressing group also showed a decrease in ORs over time, though CIs were wider and often crossed the null. The difference in linear slope between the two groups was not significantly different, implying no difference between the two groups. It may be that Aβ1-42 suppression does not fully account for differences between individual NSAIDs and that some other mechanism of action, mediated through drugs present in both groups, accounted for similar protective effects over time.
We recognize a number of limitations in our study. Our outcomes were derived from clinical visits and hospitalizations and were therefore liable to errors in coding. We attempted to account for this by using a variety of outcome definitions. Even if we missed a significant number of cases, we would have expected our results to underestimate the effect rather than showing the strong effects we observed for some NSAIDs. Drug exposure could also have been misclassified if subjects did not take medications as prescribed or used over-the-counter NSAIDs, which we could not capture. We think this is unlikely to be a significant problem with long-term prescriptions of NSAIDs. Information on confounders that could have been of relevance, such as actual socioeconomic status, education, or tobacco use, was unavailable. Some of these may be have important associations with AD.17
Confounding by indication could have occurred in this study if persons developing, but not yet diagnosed with, AD were more likely to discontinue NSAIDs than others who remained healthy. We believe there are arguments against confounding by indication as an explanation of our results. First, our data set was large enough that we could evaluate long-term use of several different NSAIDs. Some, but not all, had protective associations for AD. If confounding by indication explained our results, we should have seen similar protective effects with all NSAIDs. Second, significant bias in our results would have required that practitioners systematically recognized patients at risk of AD before they were diagnosed and avoided prescribing NSAIDs before making a diagnosis. This seems unlikely.
Our study has implications for future trials of NSAIDs in AD. Randomized trials have almost exclusively used NSAIDs whose long-term use may not be protective (e.g., rofecoxib, naproxen). It is interesting that in ADAPT, which randomly assigned patients at risk for AD to either naproxen or celecoxib, neither drug showed a definite effect, though naproxen showed a somewhat stronger trend compared with celecoxib, a finding that is consistent with the results of our study.9
Other drugs that we found to be protective, such as ibuprofen, might be good candidates for future trials.