Nice study, but confirmatory nonetheless.

View all comments by Eddie Koo

This study suggests a novel mechanism by which NSAIDs might be protective in AD, and a potentially novel and selective mechanism for lowering Ab42 production. This is important because Ab42 is thought to be a critical factor initiating Ab aggregation. -- Benjamin Wolozin

View all comments by Benjamin Wolozin

I believe this study has the potential to accelerate active AD prevention. I'm puzzeled that the re-analysis of data (see 23 July 2002 news story) discerning between NSAIDs is taking so long to be published. This has to be seen as a CORRECTION, and an ALERT and promptly made available.

View all comments by Larry Nault

The most innovative paper from 2001, which provided a novel means of modulating γ-secretase activity.

View all comments by Dominic Walsh

Many of Sidney Wolfe's accusations of ADAPT are unfounded although I appreciate their caution that giving these drugs to elderly individuals can be potentially dangerous. I will focus only on those aspects that concern our work as I think our results have been misrepresented or misinterpreted.

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

Many of Sidney Wolfe's accusations of ADAPT are unfounded although I appreciate their caution that giving these drugs to elderly individuals can be potentially dangerous. I will focus only on those aspects that concern our work as I think our results have been misrepresented or misinterpreted.

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 proposed beneficial effects of NSAIDs in humans is a stretch, to say the least.

Third, we have never discounted the inflammatory responses. We never claimed the inflammatory responses are a result of AD. Even if the inflammatory responses are secondary doesn't mean that modulating these responses cannot alter the risk for AD or the disease course. It is likely that AD treatment must be approached via different angles.

Finally, reanalysis of the Rotterdam study did not take into account our results of all the FDA-approved NSAIDs. The authors assumed that all compounds not mentioned as positive must therefore be negative, which is incorrect (though not their fault, we just didn't have all the data when our Nature paper came out). Even if true, Wolfe ignored the fact that the confidence level is a lot lower in the reanalyzed data.

View all comments by Eddie Koo

Dear John,

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

Dear John,

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 3) the NSAIDs that are being used in the ADAPT trial were not effective in preventing disease progression.

1. The inflammatory hypothesis no longer holds…

There is ample evidence that inflammation processes do play a role in Alzheimer's disease. Whether inflammation is causal, contributes to the progression of the disease, or merely marks the ongoing pathologic process is unclear. The fact that amyloid deposition in the brain triggers a local inflammatory response does not preclude that inflammation may contribute to disease initiation or progression. Our observation in the Rotterdam Study that persons with higher high plasma levels of inflammatory proteins were at an increased risk of dementia and Alzheimer's disease is compatible with inflammation contributing to the pathogenesis of dementia.

It is highly likely that Aβ accumulation in the brain does play a central role in Alzheimer's disease. However, what causes this accumulation in the majority of cases is largely unclear. Alzheimer's disease is a multifactorial and heterogeneous disorder. This implies that there is no single cascade of events that ultimately leads to the clinical syndrome. Moreover, it implies that there may be different mechanisms on which one could intervene to prevent or delay onset of disease.

Most basic research focuses on specific Alzheimer pathology. However, there is now convincing evidence that the larger proportion of elderly dementia patients actually has a mixture of degenerative as well as vascular pathologies in their brains that may all have contributed to the clinical syndrome. Prevention of vascular pathology may be an effective strategy to postpone onset of clinical Alzheimer's disease. Since inflammation is involved in the occurrence and progression of atherosclerosis, anti-inflammatory strategies might prove effective in the prevention of Alzheimer's disease through an effect on vascular pathology.

2. Some NSAIDs lower Aβ, others do not.

Observations that some specific NSAIDs do have an effect in vitro or mice on amyloid processing are extremely interesting. However, they do not rule out that those or other NSAIDs may also have effects on different yet relevant mechanisms. Also, it is unknown whether the NSAIDs that lowered Aβ have an effect on amyloid processing in humans.

Triggered by the cell culture and mouse observations, we re-analyzed the Rotterdam Study data. Our findings in that re-analysis are compatible with the view that different NSAIDs may have different effects on risk of Alzheimer's disease. However, our findings should be interpreted carefully. As in any observational study, there may have been residual confounding. Also, we had limited power. The lab and epidemiological data strongly suggests that this is a research area that merits further investigation.

As yet there is no proof that lowering Aβ levels reduces the risk of Alzheimer's disease, nor that that might be achieved through specific NSAIDs.

The NSAIDs being used in ADAPT were ineffective in preventing disease progression. The fact that a drug is not effective in stopping progression of overt disease does not imply that the drug may not be effective at a completely different stage. Indeed, since different processes are likely to be involved at different stages of the disease, it is to be expected that drugs that prevent onset of disease have no effect on disease progression and vice versa.

View all comments by Monique MB Breteler

I have read the letter and was quite distressed by it. I am not involved in the ADAPT, though I have had a number of discussions with John Breitner about it, and have shared data from the ADCS NSAID study with the ADAPT investigators. Also, I was involved with the NIA review of the ADAPT application.

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

I have read the letter and was quite distressed by it. I am not involved in the ADAPT, though I have had a number of discussions with John Breitner about it, and have shared data from the ADCS NSAID study with the ADAPT investigators. Also, I was involved with the NIA review of the ADAPT application.

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 inflammation and anti-inflammatory drugs in AD. I believe that this new line of evidence warrants further investigation, perhaps including clinical studies.

It is quite difficult, though not necessarily impossible, to alter a large clinical trial that is under way. One major issue is expense: it would require a huge additional investment to add an ibuprofen arm. Indomethacin would probably not be a good choice, because of toxicity concerns. Ibuprofen or sulindac would be preferable. I believe that discussion of additional trials that would test the hypothesis that ibuprofen or sulindac can favorably alter the course of AD is appropriate at this time.

View all comments by Paul Aisen

The addition of a third arm with ibuprofen is a consideration. It would be logistically difficult but possible to do. The real question is does ibuprofen make any more sense than naproxen since tolerated doses over five years may well be too low to block formation of Aβ42.

View all comments by Leon Thal

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

This is the fifth published trial of antiinflammatory treatments for disease modification or symptomatic improvement in Alzheimer's dementia. Two early small studies showed an encouraging suggestion of disease modification (slowing or progression) in patients randomized to indomethacin and diclofenac. These trials encountered severe difficulties, however, with high rates of dropouts, and they were too small, in any case, to produce definitive results.

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

This is the fifth published trial of antiinflammatory treatments for disease modification or symptomatic improvement in Alzheimer's dementia. Two early small studies showed an encouraging suggestion of disease modification (slowing or progression) in patients randomized to indomethacin and diclofenac. These trials encountered severe difficulties, however, with high rates of dropouts, and they were too small, in any case, to produce definitive results.

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 null.

With the benefit of more recent laboratory data, there are reasons to wonder whether the alleged beneficial effects of NSAIDs on AD dementia could relate to activities of these compounds other than their inhibition of cyclooxygenases. In this connection, it is unfortunate that there has been no trial yet published of ibuprofen for AD treatment. In a broad range of observational studies, ibuprofen is the agent most widely associated with reduced risk of incident AD, and the laboratory data suggest that, among widely used NSAID agents, ibuprofen may have particular advantages in its influence on Aβ formation and possibly on glutamate uptake through its influence on PPARγ. Particularly in view of the findings produced by ibuprofen in Tg2597 transgenic mice, I believe that a treatment trial with ibuprofen is needed before we should sound the "death knell" for treatment trials with antiinflammatory agents.

More importantly, however, I would note that all of the above trials have tested various agents for the treatment of Alzheimer's dementia, whereas all of the observational data suggest that NSAIDs may reduce the risk of incident dementia, i.e., may protect those at risk from the progression of the AD pathogenetic pathway, from its latent stages (believed to occur over a period of decades) through the recognized AD prodrome of mild cognitive impairment (MCI), and eventually to onset of AD dementia. While laboratory evidence might offer some hope that NSAIDs could mitigate disease pathogenesis after the onset of dementia, the epidemiological data offer no support for this perspective. Instead, they suggest that NSAIDs may be effective for the prevention (not treatment) of AD dementia. Therefore, the most promising avenue for future research with NSAIDs in AD would appear to lie with their being tested for prevention. Such prevention could either operate from the point when individuals have developed MCI (i.e., from the standpoint of AD dementia, secondary prevention) or in yet earlier pathogenetic stages that are still symptomatically silent (primary prevention). The Alzheimer's Disease Antiinflammatory Prevention Trial, or ADAPT, is testing two NSAIDs, naproxen and celecoxib, for their safety and efficacy in preventing AD dementia in asymptomatic individuals. Given the recent laboratory data, it may be that a similar trial using ibuprofen would be justified.

View all comments by John Breitner

The study by Aisen et al. shows no benefit to rofecoxib or naproxen in patients with mild to moderate AD. Nevertheless, this negative study is an important contribution to the collective effort to evaluate therapeutic strategies to treat or prevent AD. The excellent discussion highlights the salient points and limitations of this study:

• 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
  

The study by Aisen et al. shows no benefit to rofecoxib or naproxen in patients with mild to moderate AD. Nevertheless, this negative study is an important contribution to the collective effort to evaluate therapeutic strategies to treat or prevent AD. The excellent discussion highlights the salient points and limitations of this study:

• 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 to have efficacy in animal models may still be warranted.
• Prevention studies of NSAIDs, especially those that lower Ab42, may be warranted.
• NSAID use in an elderly population that is associated with risk of morbidity.

Of note, although not published, both Merck and Pharmacia have conducted or are still conducting therapeutic trials with rofecoxib and celecoxib, respectively. Preliminary data presented at some meetings is consistent with a lack of efficacy of these agents.

From our perspective, we believe that it is important to consider testing ibuprofen in both therapeutic and prevention trials. Although there are no rigorous statistical data from the epidemiology studies that prove that ibuprofen use was associated with the reduction in risk, it is generally believed that the majority of long-term NSAID users will, in fact, be taking ibuprofen. Furthermore, ibuprofen is the only approved NSAID that has been tested in AD animal models and shown to be of benefit. The only current prevention trial of NSAIDs (ADAPT evaluating naproxen and celecoxib) is not administering a compound that alters Ab42 production. Moreover, neither of the agents in the ADAPT trial have been shown to have a beneficial effect in AD animal models.

View all comments by Todd E. Golde
View all comments by Eddie Koo

The recent report by Kukar et al. provides compelling evidence that some GSMs can modulate γ-secretase activity by binding the APP-CTF. The authors propose that the binding of GSMs to the APP-CTF induces conformational changes in the PS1/γ-secretase when the GSM-bound substrate enters the complex. As pointed out by Golde and colleagues, these exciting new findings nicely support our previous studies (Tesco et al., 2005) showing that the APPV715F substitution in the APP transmembrane domain mimics the effects of Aβ42-lowering NSAIDs, by reducing the ratio of Aβ42:Aβ40. This same substitution affected AICD production and PS1 conformation in a similar way to that of NSAIDs. These data suggested that the Aβ transmembrane domain might serve as a target for γ-secretase modulation.

Phenylalanine-scanning mutagenesis of the APP transmembrane domain (TMD) had previously shown that APPV715F substitution shifts Aβ cleavage toward the production of the less fibrillogenic species Aβ38, while decreasing levels of Aβ40 and even more...  Read more

The recent report by Kukar et al. provides compelling evidence that some GSMs can modulate γ-secretase activity by binding the APP-CTF. The authors propose that the binding of GSMs to the APP-CTF induces conformational changes in the PS1/γ-secretase when the GSM-bound substrate enters the complex. As pointed out by Golde and colleagues, these exciting new findings nicely support our previous studies (Tesco et al., 2005) showing that the APPV715F substitution in the APP transmembrane domain mimics the effects of Aβ42-lowering NSAIDs, by reducing the ratio of Aβ42:Aβ40. This same substitution affected AICD production and PS1 conformation in a similar way to that of NSAIDs. These data suggested that the Aβ transmembrane domain might serve as a target for γ-secretase modulation.

Phenylalanine-scanning mutagenesis of the APP transmembrane domain (TMD) had previously shown that APPV715F substitution shifts Aβ cleavage toward the production of the less fibrillogenic species Aβ38, while decreasing levels of Aβ40 and even more dramatically, levels of Aβ42 (Lichtenthaler et al., 1999). We also found that the APPV715F substitution does not affect AICD production, but significantly increases the distance between the N- and C-termini of PS1, as assessed by FLIM analysis. The transmembrane domain of APP has been postulated to adopt an α-helix (Lichtenthaler et al., 1999; Qi-Takahara et al., 2005).

Since amino acid substitutions in the APP transmembrane domain may change its helical conformation, in the discussion section of our paper, we hypothesized that amino acid substitutions in the TMD of APP can produce a change in PS1 conformation, e.g., the APPV715F substitution induces an Aβ1-38-favoring conformation that shifts γ-secretase cleavage away from Aβ42 production. Accordingly, we suggested that the Aβ42-lowering NSAIDs may not necessarily target the PS1/γ-secretase complex, but instead bind to the transmembrane portion of APP, altering its helical conformation, which, in turn, alters the conformation of the PS1/γ-secretase complex. In the conclusion of our paper we suggested “that an allosteric modulation of γ-secretase shifting Aβ generation toward the less fibrillogenic Aβ1-38 may be achieved by small compounds targeting not only PS1 and/or other components of the γ-secretase complex, but also APP.” The excellent new study from Kukar et al. provides exciting new data clearly supporting this hypothesis.

References:
Tesco G., Ginestroni A., Hiltunen M., Kim M., Dolios G., Hyman B.T., Wang R., Berezovska O., Tanzi R.E. APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation. J. Neurochem. 2005 Oct;95(2):446-56. Abstract

Lichtenthaler SF, Wang R, Grimm H, Uljon SN, Masters CL, Beyreuther K. Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3053-8. Abstract

Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005 Jan 12;25(2):436-45. Abstract

View all comments by Giuseppina Tesco