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

The main purpose of our Neurology study was to determine tolerability in AD of nimesulide, a NSAID preferentially inhibiting cyclooxygenase (COX)-2 but also, to a lesser degree, COX-1. The study was designed to test if nimesulide is suitable in chronic treatment. This is a fundamental question for the use of anti-inflammatory drugs in AD because the poor tolerability of all the currently tested non-steroidal anti-inflammatory drugs in elderly, frail AD patients does not allow a long-term, efficacious treatment plan in these patients. The study was supported by Helsinn Healthcare SA.

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

The main purpose of our Neurology study was to determine tolerability in AD of nimesulide, a NSAID preferentially inhibiting cyclooxygenase (COX)-2 but also, to a lesser degree, COX-1. The study was designed to test if nimesulide is suitable in chronic treatment. This is a fundamental question for the use of anti-inflammatory drugs in AD because the poor tolerability of all the currently tested non-steroidal anti-inflammatory drugs in elderly, frail AD patients does not allow a long-term, efficacious treatment plan in these patients. The study was supported by Helsinn Healthcare SA.

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 found no adverse effect of nimesulide on cognition, an important consideration with a CNS-penetrating drug. Further, there was no significant adverse effect on clinical stage (CDR), activities of daily living, mood, or behavior.

A secondary analysis, which is ongoing, concerns the impact of nimesulide on specific items of the assessment scales among those who completed the 12 week phase on full-dose therapy without interruption. As with the intent-to-treat analysis, there was no significant difference between groups on any of the total outcome measures. However, analysis of individual items revealed differences between nimesulide and placebo. These pos-hoc analyses of item scores suggest that nimesulide treatment had a favorable effect on judgment, orientation, and sleep. But while the raw p values suggest statistical significance, it must be noted that these are not corrected for the large number of comparisons.

Because of the high tolerability, a compassionate use phase program was offered at the end of the scheduled double-blind and open-label phases. The timing of visits during the compassionate use phase was somewhat irregular, so we estimated rate of decline at 12, 24, 52, 78 and 104 weeks using a 4-week margin around these target intervals. For comparison, we generated estimates of expected decline over these intervals using the annual rate of decline of historical controls in studies performed in our institution, adjusted for baseline ADAScog score. We found that nimesulide treatment over the course of 104 weeks compared favorably to the course of disease progression in historical controls. We point out that this comparison to historical controls has questionable validity, which may be particularly true in this instance, as the control study was conducted prior to the availability of donepezil, which may reduce the rate of cognitive decline (88 percent of subjects in this study were concomitantly treated with donepezil).

In conclusion, our study suggests that nimesulide therapy is well-tolerated in the AD population, in contrast to other, non-selective NSAIDs for periods exceeding 2 years. Most importantly, the rate of cognitive decline of subjects on nimesulide compares favorably to published data on historical, untreated controls followed in our department at Mount Sinai School of Medicine. Interestingly, we also found that post-hoc analysis of individual items suggests possible benefit on clinical assessment of orientation and judgment, and possible mood elevation in response to short-term therapy with nimesulide, compared to placebo. Helsinn Healthcare SA and I are considering a further efficacy study to fully assess the potential of nimesulide in treatment of Alzheimer's.

View all comments by Giulio Pasinetti

The epidemiology supporting an association of chronic and early NSAID use with reduced risk for AD is consistent enough to take seriously. Results from the recent Rotterdam and Cache County studies, as well as many others, suggest that risk for AD can be reduced to about one fifth compared to control populations. This is without optimization of NSAID choice, dose, or time of intervention, suggesting that even more risk reduction would result from optimization of NSAID use.

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

The epidemiology supporting an association of chronic and early NSAID use with reduced risk for AD is consistent enough to take seriously. Results from the recent Rotterdam and Cache County studies, as well as many others, suggest that risk for AD can be reduced to about one fifth compared to control populations. This is without optimization of NSAID choice, dose, or time of intervention, suggesting that even more risk reduction would result from optimization of NSAID use.

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 favorable toxicity profile with nimesulide, a widely used mixed COX-1 and COX-2 inhibitor.

These new clinical trial results show no short-term effect on cognition, but the authors suggest that long-term nimesulide use may slow disease progression. This is a testable hypothesis, and based on nimesulide's demonstrated neuroprotective and anti-inflammatory effects in animal models. While it is hard to imagine a downside to neuroprotective activity, the relative importance of a range of potentially beneficial NSAID effects on AD pathogenesis remains uncertain. In addition to control of reactive microglia and direct neuroprotection, a number of other relevant potentially important NSAID activities have been observed, including effects on amyloid production, on pro-amyloidogenic factors (ApoE, ACT) and on amyloid phagocytosis/clearance. Whether NSAIDs proposed for use in AD have these or other AD-relevant activities at acceptable doses should be an active area of investigation. More work needs to be done at the preclinical level.

View all comments by Gregory Cole

This is the third small report of a trial of a non-steroidal anti-inflammatory drug (NSAID) for the treatment of AD. As in each prior study, the intent was to test the efficacy of an NSAID (in this instance, the COX-2 preferential agent nimesulide) for improvement in symptoms of AD over a relatively brief time span. In the present instance, somewhat more emphasis was placed also on assessing the tolerability of the treatment in often-frail elderly with AD.

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

This is the third small report of a trial of a non-steroidal anti-inflammatory drug (NSAID) for the treatment of AD. As in each prior study, the intent was to test the efficacy of an NSAID (in this instance, the COX-2 preferential agent nimesulide) for improvement in symptoms of AD over a relatively brief time span. In the present instance, somewhat more emphasis was placed also on assessing the tolerability of the treatment in often-frail elderly with AD.

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 (Scharf et al., 1999) and (especially) indomethacin (Rogers et al, 1993).

Although suggesting a therapeutic benefit, the results of the indomethacin trial were of questionable interpretation because of the experiment's very high drop-out rate and the method of statistical analysis, which combined four non-informative results post hoc into an aggregate outcome that was marginally "statistically significant." The diclofenac results were ambiguous for efficacy. The present results are less hopeful but, as an offset, suggest the best tolerability yet observed in a published NSAID trial. All three trials were under-powered, but one might have hoped here for a weak signal suggesting efficacy. If the results are interpreted literally, they seem to suggest greatest efficacy with the COX-1 selective agent indomethacin, weaker effect with the relatively balanced agent diclofenac, no apparent benefit with COX-2 selective nimesulide, and the inverse order for tolerability. The present observations fit with the null results (but relatively good tolerability) reported from an unpublished large one-year trial of the specific COX-2 inhibitor celecoxib.

Clearly, more data are needed from adequately powered trials on this important topic. Given the above, these trials should include agents targeting COX-1. Presumably, commercial considerations have precluded the initiation of a trial of ibuprofen, the agent with the greatest body of epidemiological evidence to suggest its benefit. Such a trial is clearly needed. Also important will be trials for efficacy of NSAIDs' effects at earlier stages of AD pathogenesis, including the "conversion" to dementia from milder cognitive syndromes and the primary prevention of symptoms altogether.

View all comments by John Breitner

The nimesulide trial represents another failure in applying the epidemiological evidence of NSAIDs protecting against AD toward successful treatment. There are some simple explanations for this failure. First of all, a mismatch exists between the NSAIDs used in the failed clinical trials and those consumed by the cohorts studied epidemiologically. The latter all involved classical NSAIDs, which are strong COX-1 or mixed inhibitors, while the failed clinical trials, including that of nimesulide, have involved preferential COX-2 inhibitors. The COX-2 inhibitors have lower gastrointestinal side effects, but this is hardly important if the appropriate target in brain is COX-1. COX-2 in human brain is concentrated in pyramidal neurons while COX-1 is preferentially expressed in microglia, so COX-1 is the principal target. To be clinically effective, the NSAID chosen must be effective against COX-1, able to cross the blood-brain barrier, and be administered in a dose sufficient to inhibit neuroinflammation.

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

The nimesulide trial represents another failure in applying the epidemiological evidence of NSAIDs protecting against AD toward successful treatment. There are some simple explanations for this failure. First of all, a mismatch exists between the NSAIDs used in the failed clinical trials and those consumed by the cohorts studied epidemiologically. The latter all involved classical NSAIDs, which are strong COX-1 or mixed inhibitors, while the failed clinical trials, including that of nimesulide, have involved preferential COX-2 inhibitors. The COX-2 inhibitors have lower gastrointestinal side effects, but this is hardly important if the appropriate target in brain is COX-1. COX-2 in human brain is concentrated in pyramidal neurons while COX-1 is preferentially expressed in microglia, so COX-1 is the principal target. To be clinically effective, the NSAID chosen must be effective against COX-1, able to cross the blood-brain barrier, and be administered in a dose sufficient to inhibit neuroinflammation.

Indomethacin and ibuprofen are two classical NSAIDs that meet the first two criteria, but to be effective they must be administered in a sufficiently high dose. Post-mortem studies show that the degree of inflammation in AD brain is higher than in joints removed surgically for chronic arthritis. Therefore it may be that treatment doses will need to be higher than preventive doses. Side effects may be significant, but managing such side effects is preferable to not managing the deterioration in AD.

View all comments by P.L. McGeer

The involvement of an inflammatory component in AD has been amply documented over the last decade and has led to a number of clinical trials of anti-inflammatory agents. The epidemiological data clearly demonstrate that a subset of NSAIDs are effective in reducing AD risk. However, clinical trials of two COX-2 specific inhibitors, as well as the recent nimesulide study, do not yet provide compelling evidence that NSAID therapy will be therapeutically effective in AD. Moreover, and as pointed out by others, the trials have been limited by being underpowered, of short duration, and perhaps not done at the appropriate clinical stage.

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

The involvement of an inflammatory component in AD has been amply documented over the last decade and has led to a number of clinical trials of anti-inflammatory agents. The epidemiological data clearly demonstrate that a subset of NSAIDs are effective in reducing AD risk. However, clinical trials of two COX-2 specific inhibitors, as well as the recent nimesulide study, do not yet provide compelling evidence that NSAID therapy will be therapeutically effective in AD. Moreover, and as pointed out by others, the trials have been limited by being underpowered, of short duration, and perhaps not done at the appropriate clinical stage.

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, 2001). Indomethacin and ibuprofen, the NSAIDs that have been shown to exert the most significant therapeutic effect in reducing the risk and delaying the onset of AD, also bind to and activate the Peroxisome Proliferator Activated Receptor gamma (PPARγ) a member of the nuclear hormone receptor family (Lehman et al. 1997). PPARγ activation exerts strong anti-inflammatory actions in many cell types, including microglia, astrocytes, and neurons (Bernardo et al, 2000; Combs et al. 2000; Klegeris et al, 1999; Heneka et al 2000; Heneka et al. 1999). These anti-inflammatory effects of PPARγ agonists are mediated through transcriptional inhibition of proinflammatory gene expression. The mechanisms for these events have been shown to be due, in part, to scavenging of transcriptional cofactors (i.e. CBP, P300) by activated PPARγ, which therefore prevents them from interacting with inflammatory transcription factors such as NFkB and results in decreased inflammatory gene expression. Also, PPARγ activation induces expression of inhibitory IkB proteins, which would be expected to further reduce NFkB activation.

The possibility that NSAIDs exert protective actions through PPARγ activation, and not by inhibition of COXs, is supported by several studies showing that 1) non-selective NSAIDs were effective at high doses (mM) where they bind to PPARγ, but not at lower doses at which they would be expected to inhibit COX-dependent prostanoid generation; 2) direct application of COX2 selective inhibitors were without effects; and 3) direct application of selective PPARγ agonists were protective. In our studies we found that the inflammatory reaction in vitro (Combs et al. 2000) or in vivo (Heneka et al 2000) in brain was prevented by drugs that bind to and activate PPARγ (15-deoxy D12, 14-prostaglandin J2; troglitazone, and ibuprofen) but not by the COX2 inhibitor NS398.

The possibility that PPARγ activation could be therapeutically useful for the treatment of AD is particularly relevant given that two PPARγ agonists (pioglitazone and rosiglitazone) are FDA-approved for treatment of type II diabetes. This should facilitate the design and implementation of clinical trials for AD. An NIH-sponsored pilot clinical trial of pioglitazone in a small cohort of patients has recently been initiated at University Hospitals Cleveland/Case Western Reserve University.

We should also mention that oral PPARγ agonists provided protection in other neuropathological conditions that contain an inflammatory component, including EAE , the model for MS, (Niino et al, 2001, and other work in press), suggesting that at least some of these drugs can sufficiently pass through the blood-brain- barrier and exert intraparenchymal anti-inflammatory effects.

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

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

I wonder if exercise is a confounding variable in the epidemiological studies? People who exercise are probably more likely to take NSAIDs. In which case the protective effect could be from the exercise, not the NSAID.

View all comments by Ashley Bush

The Alzheimer's Association has held "odd year" (2003, 2005, 2007) meetings in D.C. for several iterations with attendance in the 2,000-person range or below. Vienna ICAD 2009 was the first iteration of an odd-year meeting that was called "ICAD" and not "Prevention." In fact, compared to the prior odd-year meetings, attendance in Vienna showed a major uptick. This was surprising, given the slow economy and the international location (U.S. meetings are always better attended than international meetings).

View all comments by Sam Gandy