ARTICLE IN BRIEF
Investigators reported than an average of two years after the ADAPT trial was stopped, follow-up results suggest that after exclusion of individuals with baseline cognitive syndromes, naproxen cuts the risk of developing Alzheimer disease by a statistically significant 67 percent.
VIENNA—Use of nonsteroidal anti-inflammatory drugs (NSAIDs) may accelerate the appearance of Alzheimer disease (AD) pathogenesis in people who already have advanced disease, but the NSAIDs may protect against the disease in people with healthier brains, researchers reported here at the International Conference on Alzheimer's Disease.
Lead investigator John C. S. Breitner, MD, MPH, professor of psychiatry and behavioral sciences and adjunct professor of epidemiology at the University of Washington in Seattle, said that is the suggestion from a follow-up analysis of a May 2007 clinical trial, published in Neurology.The Investigators had originally concluded that neither naproxen nor celecoxib preserved mental function.
The randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was one of several clinical trials conducted after observational studies demonstrated a lower incidence of Alzheimer dementia in regular users of NSAIDs.
The results of the randomized controlled trials have been “disappointing,” with some even suggesting that NSAIDs may be harmful, Dr. Breitner said. But he noted that “all but one of those trials used NSAIDs to treat patients who already had AD.”
In contrast, ADAPT was designed to be a “true primary prevention trial,” testing the hypothesis that the NSAIDs naproxen and celecoxib might be able to protect cognitively normal people against Alzheimer disease, he said.
Beginning in early 2001, 2,250 subjects were randomized to celecoxib at 200 mg twice daily, naproxen at 220 mg twice daily, or placebo. The main outcome measure was a diagnosis of Alzheimer disease after randomization.
At entry, all the participants “had to have passing scores on cognitive exams and a first degree relative with Alzheimer disease,” Dr. Breitner said.
Patients completed a cognitive assessment using the Cognitive Assessment Battery at baseline and annually thereafter. Those with low scores were brought in for a more detailed dementia evaluation and psychometric assessment.
The trial was halted early in December of 2004, after investigators in a different trial (the Adenoma Prevention with Celecoxib study), reported that celecoxib was associated with a significantly increased risk of cardiovascular disease.
The primary results, which included all events that occurred up to July 17, 2005, six months after the study was halted, failed to support the hypothesis that celecoxib or naproxen could prevent Alzheimer dementia.
Of note, Dr. Breitner said, was that imperfect screening measures led to enrollment of seven individuals with dementia. “Secondary analyses excluding these patients suggested that the NSAIDs may have been doing harm,” he said.
What many people don't know, he said, is that the researchers continued to follow the study participants after the study was halted.
Now, an average of two years after the trial was stopped, follow-up results suggest that after exclusion of individuals with baseline cognitive syndromes, naproxen cut the risk of developing Alzheimer disease by a statistically significant 67 percent, Dr. Breitner reported.
Celecoxib also appeared to help cognitive function, although that finding did not reach statistical significance.
“The early excess of cases among NSAID users certainly disappeared and was possibly reversed,” he said.
Why such different results? “The early results included patients who already had symptoms or neurodegeneration. From everything we know about the pathogenesis of Alzheimer disease, how else could patients have developed it so soon [after entering the trial],” Dr. Breitner said.
He said he “probably wouldn't be presenting these [preliminary] results were it not for the corroborative biomarker findings.”
A neuroprotective effect of naproxen was also evident in CSF measures of the Alzheimer dementia biomarkers tau and amyloid-beta-42 (A-beta-42), he reported.
In the 117 ADAPT patients from whom CSF was collected 21 to 41 months after treatment was terminated, the tau-to-A-beta ratio was reduced by more than 40 percent in the group originally assigned to naproxen, compared to patients assigned to placebo.
“As disease progresses, the tau-to-A-beta ratio is one of the best indicators of neurodegeneration,” Dr. Breitner said.
Celecoxib was not associated with a reduction in the tau-to-A-beta ratio, he added.
Dr. Breitner said he was completely surprised by the results.
The updated results suggest that “in the case of NSAIDs, prevention means primary prevention and not disease modification,” he said.
“It would appear that NSAIDs are harmful to people who already have symptoms or asymptomatic neurodegeneration. For people who are cognitively healthy, NSAIDs appear to protect against Alzheimer incidence and neurodegeneration,” he said.
Dr. Breitner stressed that the results need replication.
QUESTIONS ABOUT RESULTS
Asked to comment on the results, Miia Kivipelto, MD, PhD, associate professor at the Aging Research Center of the Karolinska Institute in Stockholm, and moderator of the session at which the findings were presented, said that even if NSAIDs do prove to have benefit, she would be reluctant to prescribe them to healthy patients.
“There are too many known side effects. It's not like diet and exercise, both of which have been shown to protect against Alzheimer disease and do not carry risks,” she said.
The oral presentation was well received with dozens of attendees gathering around Dr. Breitner afterward to ask questions and offer their opinions.
Among the many asked — and unanswered — questions: At what point do the drugs switch from being harmful to beneficial; and whether there would be greater benefit if people kept taking the drugs for a longer period of time or whether the benefit was due to actually stopping the drugs.
“There is an awful lot we don't know. But what I will say is this is the first pharmacological intervention that provokes fairly impressive changes in the occurrence of Alzheimer disease in humans,” Dr. Breitner said.