First, NSAIDs are not secretase inhibitors, as claimed in the letter. They only modulated β-secretase activity by reducing Aβ42 in favor of shorter Aβ peptides. β-secretase inhibitors have their limitations as potential therapeutics, as well, through inhibiting notch cleavage, etc.

Second, the dosage of NSAIDs we had to use to achieve this effect is very high, a key issue we have to address scientifically. What's FDA approved and what were given in the Rotterdam study are likely much lower than what we gave to the mice. Therefore, whether very high doses are necessary and achievable in humans in order to see the Aβ42 effect remains to be proven. Consequently, making a strong conclusion that our results imply that it is the Aβ42 effect that underlies the...  Read more

View all comments by Eddie Koo

I have read the public letter sent by the US advocacy group Public Citizen to the Department of Health and Human Services, asking its secretary Tommy Thompson to suspend the ADAPT trial. I appreciate the important watchdog function of lay and patient organizations, yet if they make scientific judgments these should be thoroughly founded. I profoundly disagree with the interpretation of the existing evidence and the scientific argument in mentioned letter. The authors of the letter partly base their opinion on our research findings from the Rotterdam Study, which is why I would like to comment on their arguments and give you my current views on whether anti-inflammatory drugs might be beneficial in the prevention of Alzheimer's disease.

Public Citizen postulates that there is no longer any biological basis for the ADAPT trial. Their arguments include that 1) the inflammatory hypothesis of AD no longer holds and Aβ accumulation is central to Alzheimer's disease; 2) there is convincing evidence now that some NSAIDs do lower Aβ, whereas others do not; and...  Read more

View all comments by Monique MB Breteler

I would describe the letter as an inflammatory tirade rather than a scientific argument. While it does review some relevant scientific observations, the discussion is one-sided. I do not agree with the conclusions and recommendations of the letter. Celecoxib and naproxen were chosen based on a number of considerations, including epidemiologic data suggesting that NSAIDs reduce the risk of AD, and basic research suggesting that a number of inflammatory processes, including cyclooxygenase activity, may contribute to neurodegeneration in AD, as well as tolerability issues.

The recent evidence suggesting that a subset of NSAIDs favorably influence AβPP processing is quite interesting, and may be important. But it represents one recent addition to a huge body of data on...  Read more

View all comments by Paul Aisen

The primary analysis of the influence of nimesulide on cognition was covariance analysis, with baseline ADAScog score as a covariate, to assess change in ADAScog during treatment in the nimesulide group versus the placebo group. There was no difference in cognitive decline between groups. We note, however, that at 12-week double-blind phase, only a symptomatic benefit (as seen with cholinesterase inhibitors such as donepezil) would be likely to be detected. Analysis of the 12-week time point...  Read more

View all comments by Giulio Pasinetti

A major obstacle to more widespread use of NSAIDs for AD prevention is toxicity, particularly in the elderly. Both COX-1 and COX-2 targets are arguably important in AD pathogenesis. The positive epidemiology relies entirely on mixed COX inhibitors, suggesting they should be tested. Toxicity, particularly of mixed COX inhibitors, has been a significant limiting factor in previous NSAID trials in AD. To date, the option of using less toxic COX-2 specific inhibitors has failed to produce good results. Therein lies the significance of this Neurology report from Aisen et al., which demonstrates a relatively...  Read more

View all comments by Gregory Cole

Participants were observed in the masked portion of this trial for 12 weeks, with a follow-on period of open label observation lasting another 12 weeks. Neither the masked, placebo-controlled portion or the trial, nor the 24-week assessment of symptoms before and after treatment showed any hint of therapeutic benefit. This may not be surprising, given the size and the relatively short duration of treatment in this trial, but it is disappointing nonetheless. A more hopeful outcome is that this agent was better tolerated than the drugs tested previously, diclofenac (  Read more

View all comments by John Breitner

Indomethacin and ibuprofen are two classical NSAIDs that meet the first...  Read more

View all comments by P.L. McGeer

One aspect of this issue that has not been discussed in this forum is the existence of other potential targets of NSAIDs that could account for their therapeutic effects (Heneka et al. 2001, Landreth and Heneka,...  Read more

View all comments by Douglas Feinstein

NSAIDS, ALZHEIMER'S DISEASE AND PUBLIC CITIZEN

With regard to this news item please see my Open letter to Public Citizen's Health Research Group on Alzheimer's disease research. Science SAGE KE (21 Feb., 2003) [ Full Text ] ; BMJ (27 Feb., 2003) [ Full Text ] .


View all comments by Alexei R. Koudinov

More recently published trials have tested low-dose prednisone, a broad-spectrum corticosteroidal antiinflammatory agent, and hydroxychloroquine, an antimalarial drug that is widely acknowledged to have potent antiinflammatory activity. The prednisone trial showed a predictable range of safety concerns, but the treated group showed worse performance, if anything, on their measures of disease progression. The hydroxycholoroquine trial results were null, despite that trial's having especially abundant statistical power to demonstrate a relatively modest level of benefit. This latest trial with rofecoxib and naproxen is again...  Read more

View all comments by John Breitner

• The epidemiologic data supports a role for NSAIDs in prevention of AD and not in treatment. Thus, it is not necessarily surprising that no benefit was observed in this patient trial.
• The most consistent reduction of risk in the epidemiologic studies of NSAIDs and AD was in the group that used NSAIDs for greater than two years; thus, it is possible that a one-year study with any NSAID will not show a beneficial effect.
• Unlike some other NSAIDs (ibuprofen), rofecoxib or naproxen do not lower Ab42. They also have not been reported to have any beneficial effect in AbPP mouse models.
• Treatment trials with other NSAIDs that reduce Ab42 and are proven...  Read more
  
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