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