The ADAPT trial was a bold attempt to determine if cyclooxygenase (COX) inhibitors could prevent cognitive decline, but it was flawed from the start by the unfortunate choice of celecoxib and naproxen as the agents to test. Celecoxib should never have been chosen for this or any other AD clinical trial. There is no epidemiological evidence to support such a choice, and there are strong contraindications from basic research against its use. The same applies to all selective COX-2 inhibitors. COX-2, in contrast to COX-1, is an essential enzyme for normal physiological functioning. That was revealed when COX-2 knockout mice died prematurely from kidney failure and cardiac fibrosis (1), while COX-1 knockout mice had a normal life span. This information was known before the coxibs were introduced clinically and presaged the later withdrawal of Vioxx due to cardiac complications.

Brain is one of the few areas in the body that constitutively expresses high levels of COX-2, again signifying an important physiological function (2). It is concentrated in the very pyramidal neurons that...  Read more

The ADAPT trial was a bold attempt to determine if cyclooxygenase (COX) inhibitors could prevent cognitive decline, but it was flawed from the start by the unfortunate choice of celecoxib and naproxen as the agents to test. Celecoxib should never have been chosen for this or any other AD clinical trial. There is no epidemiological evidence to support such a choice, and there are strong contraindications from basic research against its use. The same applies to all selective COX-2 inhibitors. COX-2, in contrast to COX-1, is an essential enzyme for normal physiological functioning. That was revealed when COX-2 knockout mice died prematurely from kidney failure and cardiac fibrosis (1), while COX-1 knockout mice had a normal life span. This information was known before the coxibs were introduced clinically and presaged the later withdrawal of Vioxx due to cardiac complications.

Brain is one of the few areas in the body that constitutively expresses high levels of COX-2, again signifying an important physiological function (2). It is concentrated in the very pyramidal neurons that are vulnerable in AD (3). Despite these facts, four COX-2 inhibitor trials in AD have been carried out, all of them predictably ending in failure. Only recently has it come to light that in the rofecoxib trials, there was a 2.85-fold increase in mortality in AD patients compared to controls (4).

The negative effects of naproxen may have been less predictable at the outset of the ADAPT trial, but there was no epidemiological evidence to favor its selection over other traditional NSAIDs where such evidence did exist (5). To date, 25 epidemiological studies have been published showing a protective effect of traditional NSAIDs against AD, and nine have been published showing a beneficial treatment effect in transgenic mouse models of the disease. For the latest published review, see (6). Better treatments for AD are urgently needed, as are better strategies for taking basic science to the bedside.

References:
1. Dinchuk JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington MB, Contel NR, Eng VM, Collins RJ, Czerniak PM, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 1995; 378: 406-409. Abstract

2. Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, Isakson P. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Nat Acad Sci USA 1994; 91: 12013-12017. Abstract

3. Yasojima K, Schwab C, McGeer EG, McGeer PL. Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res 1999; 830:226-236. Abstract

4. Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment. JAMA 2008; 299: 1813-1817. Abstract

5. Anthony JC, Breitner JC, Zandi PP, Meyer MR, Jurasova I, Norton MC, Stone SV. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 2000; 54: 2066-71. Abstract

6. McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiol Aging 2007; 28: 639-647. Abstract

View all comments by P.L. McGeer

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