NSAIDs and Amyloid Plaques Have Close Relationship

New imaging data may help explain why nonsteroidal anti-inflammatory drugs (NSAIDs) seem to lower the relative risk for developing Alzheimer’s disease (AD).

To the surprise of researchers, two of the most common NSAIDs appear to bind directly to the amyloid plaques that are an anatomical hallmark of AD, and evidence indicates the drugs not only prevent further deposit of amyloid, but may actually break up existing plaque.

Several previous studies have indicated that AD is less prevalent in persons taking NSAIDs, said Gary Small, M.D., Parlow-Solomon Professor of Aging and professor of psychiatry and biobehavioral sciences at the University of California at Los Angeles.

“The question is,” Small told Psychiatric News, “how does that happen?”

Researchers and clinicians have postulated, Small said, that the people who take NSAIDs are typically more active and are taking the drugs for joint pains. The AD benefit gained, he said, could be related to those individuals’ better-than-average physical conditioning. “But there’s really no evidence yet to sort all of it out,” he noted. Others believe that the reduction in the prevalence of AD is a direct effect of reducing inflammatory processes in an Alzheimer’s-diseased brain.

“Clinical trials using these drugs in [patients who already have] Alzheimer’s disease have been negative,” Small added. “What we don’t know yet is how the placebo-controlled trials that are preventive in nature will come out.”

The largest such trial, the National Institute on Aging’s Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) is recruiting patients. Results from that trial are still years away.

Small and his colleagues took tissue from known Alzheimer’s-diseased brains and added two NSAIDs—naproxen and ibuprofen—and then added the chemical marker FDDNP. The marker was developed at UCLA to bind specifically to amyloid plaques to image the pathological lesions using PET scans (Psychiatric News, December 21, 2001).

What they found, Small said, was that the drugs directly bound to the amyloid-plaque formations. Additional test-tube studies with FDDNP, synthetic amyloid, and the two NSAID drugs showed that the drugs actually may dissolve the plaques and even inhibit new plaque formation.

Small and principal author Jorge Barrio, M.D., professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, published their report in the March 31 issue of Neuroscience.

“I think what is interesting and novel about our study,” Small said, “is that it suggests an alternate mechanism for how these drugs might affect the disease.” If you could actually look at an amyloid plaque, Small explained, “what you’ll see is that there is a core plug consisting of insoluble amyloid protein and around it are elements of inflammation. The thinking was that the insoluble amyloid accumulates in the brain, and then the brain tries to get rid of it through an inflammatory response. We already know that there’s something about that inflammatory response that is toxic to neurons, so let’s just get rid of the inflammatory response.”

It might not be all that straightforward, if Small’s data pan out. “It may not be the way that they are working at all,” he continued. “The NSAIDs may be getting into the insoluble amyloid core and preventing amyloid from aggregating or even dissolving what’s already there.”

He noted, however, that there is no evidence that getting rid of existing plaques will improve a patients clinical outcomes. Some researchers suspect that by the time an actual plaque is formed, the damage has occurred and cannot be repaired. What Small thinks is more exciting is the possibility that NSAIDs could prevent the original buildup of the plaques.

“These studies suggest a previously unsuspected way in which the nonsteroidal anti-inflammatory drugs may interact with Alzheimer’s amyloid,” agreed ADAPT principal investigator, John Breitner, M.D., professor and head of the division of geriatric psychiatry, psychiatry, and behavioral sciences at the University of Washington in Seattle. “They also show that different drugs in this class may have different effects on amyloid. Clearly, we have a great deal to learn about the way in which these drugs may prevent Alzheimer’s disease. The UCLA work appears to open a whole new avenue of investigation in this important area.”

The next step, Small told Psychiatric News, is to prospectively use FDDNP and PET scanning in patients who do not yet have AD, but perhaps are at high risk, and treat those patients acutely with naproxen to see if the pictures change. After that, a new treatment trial could include serial scans in patients treated with naproxen to see the long-term effects.

An abstract of Barrio and Small’s study is posted on the Web at www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12617976&dopt=Abstract. More information on the ADAPT clinical trial is posted at www.2stopad.org/. ▪