Inflammation May Hold Key to Cognitive Decline in Alzheimer's Disease

A new study poses an intriguing question: Does gum disease accelerate cognitive decline in the early stages of Alzheimer's disease? The answer may be found in inflammation.

Aging affects our immune system, and inflammation is a normal part of the body's immune response to infection or injury. Previous studies have shown that the inflammation response increases as we age. Inflammation is now linked to a number of diseases more common in people over age 65, including atherosclerosis, osteoarthritis and Alzheimer's.

In a recent study, Professor Clive Holmes of the University of Southampton (UK), along with colleagues from King's College London, conducted cognitive assessments of 60 patients with mild to moderate Alzheimer's disease. They examined patients' dental health and took blood samples to measure inflammatory markers. They retested everyone in six months, and found that patients with gum disease had a six-fold rate of cognitive decline, along with an increase in systemic inflammation.

Professor Holmes previously showed that the degree of systemic inflammation, as measured by an inflammatory molecule in the blood called TNF-alpha, correlated with the pace of cognitive decline in people with Alzheimer's disease. Indeed, many of the people who did not have elevated TNF-alpha in their blood did not decline at all during the study.

In fact, we have known that inflammation is involved in the progression of Alzheimer's for many years, so why don't we have drugs to stop it? In the early 2000s, studies showed that non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen were able to reduce neuroinflammation and the accumulation of beta-amyloid plaques in mice. At around the same time, analyses of health patterns in humans showed a correlation between taking NSAIDs and a significantly reduced risk of developing Alzheimer's. Based on these findings, researchers initiated clinical trials for Alzheimer's with various NSAIDs and other drugs known to reduce inflammation, including corticosteroids. The National Institute on Aging (NIA) funded the "ADAPT" study, involving 2,400 volunteer participants given naproxen, ibuprofen or a placebo. In all, 16 clinical trials of drugs targeting inflammation to treat Alzheimer's were undertaken.

Despite the hope that we had found a way to halt or slow Alzheimer's disease by targeting brain inflammation, all 16 trials failed, and some even showed negative effects. By 2004, the NIA announced that it suspended the use of the two NSAIDs in its study due to safety concerns.

After these dismal results, many in the Alzheimer's research community focused their efforts on other drug targets. In hindsight, perhaps the drugs tested in the trials weren't the right ones--maybe they did not get into patients' brains and affect the right inflammatory processes or maybe the trials weren't done correctly. Research has shown that special cells called microglia are the primary culprits in neuroinflammation (brain inflammation). Microglia are brain cells that play a number of helpful roles, including the destruction of beta-amyloid plaques -- a process called phagocytosis. But they can also be harmful. As microglia become more active, they release a range of toxic substances that damage neurons. They also secrete proteins known as cytokines, which are involved in inflammation and can also damage and destroy nerve cells.

Today, armed with this knowledge, we are in an era of renewed interest in drugs targeting neuroinflammation and several new approaches hold promise. In my organization, the Alzheimer's Drug Discovery Foundation (ADDF), the neuroinflammation program is the second largest in our research portfolio. Our funded researchers are both developing new drugs with specific neuroinflammation-related targets, and repurposing drugs that have been shown to target systemic inflammation in other diseases.

One example of a repurposed drug is etanercept, which Dr. Holmes (who led the dental health study) is now testing in a phase 2 clinical trial against Alzheimer's-related inflammation. This drug, already approved to treat rheumatoid arthritis, has been shown to inhibit microglial activation and positively affect cognition in preliminary studies. Other clinical trials are testing drugs that promote the removal of amyloid plaques from the brain. Yet other researchers are developing novel small molecule drugs that inhibit microglial activation by targeting a cell receptor on microglia that is involved in the production of cytokines. Still another is attempting to use a drug to stimulate cannabinoid-2 receptors on microglia to reduce inflammation.

These are only a fraction of the promising approaches being tested by ADDF-funded investigators and others in this renaissance of drug discovery targeting inflammation. In a few short years, we will know if these new drugs are effective in combating inflammation and treating Alzheimer's. And inflammation is just one of several targets we are pursuing to treat Alzheimer's, which has multiple causes. In surveying the landscape of the talented researchers developing drugs for Alzheimer's, it is my belief that it will be treatable very soon.