Both Boosting, Dampening Immune System Show Potential Against Alzheimer’s

by Aalok Mehta

September 10, 2009

In the quest for new Alzheimer’s treatments, the key may be to dial down the immune system. Or it may be to increase immune activity against the clumps of toxic amyloid proteins believed to underlie the disease. New research studies offer support to both of these seemingly contradictory approaches.

The findings help paint a picture of Alzheimer’s as a complex disease where early failures of the immune system are exacerbated by later overactivity, but which also offers several potential lines of attack.

For instance, some anti-immune strategies involve dampening the inflammation that accelerates the course of Alzheimer’s disease after initial damage to brain cells has already begun. In a recent study in Archives of Internal Medicine, researchers found that certain angiotensin-converting enzyme (ACE) inhibitors, which are commonly used to treat high blood pressure, seem to protect against dementia, possibly by reducing such inflammation.

For the study, the researchers analyzed data from about 1,000 patients taking blood pressure drugs. Those treated with centrally active ACE inhibitors—that is, drugs that cross the protective blood-brain barrier, including captropril, fosinopril and several others—showed about 65 percent less cognitive decline for each year of treatment than those taking a different blood-pressure drug.

Reduced inflammation is the likely cause, but there might be other explanations, says lead investigator Kaycee Sink, an assistant professor of internal medicine and gerontology at the Wake Forest School of Medicine. “ACE inhibitors that cross into the brain from the blood may reduce the risk of dementia by decreasing inflammation, by improving blood flow in the brain via its effects on angiotensin II, which is a vasoconstrictor, or by other mechanisms that have yet to be fully worked out,” she says.

Still, she adds, “if these results are confirmed with a clinical trial, centrally active ACE inhibitors would offer another therapeutic option for prevention of dementia that could be added to non-drug approaches such as exercise and cognitive stimulation.”

Antibody attack

When researchers look even earlier into Alzheimer’s disease progression, though, the preferred plan of attack shifts to enhancing the body’s immune reaction against amyloid before it has a chance to cause problems.

For instance, a paper appearing on July 6 in Proceedings of the National Academy of Sciences found evidence for naturally occurring neuroprotective antibodies against beta-amyloid, the protein that clumps up in Alzheimer’s disease, creating sticky plaques that interfere with neuron communication and that eventually cause cell death.

These antibodies tend to decrease as people age–but drop even further in cases of Alzheimer’s disease—the researchers found, leading them to suggest that boosting the production of the antibodies or administering them passively in the elderly may serve as an effective preventive against Alzheimer’s.

Likewise, researchers recently found that dementia occurs less in people taking intravenous immunoglobulin, or IVIg, an antibody cocktail used to treat immune deficiencies, certain cancers and some autoimmune diseases.

Writing in the July 21 issue of Neurology, Howard Fillit, a professor of neurobiology at Mount Sinai School of Medicine, and his colleagues reported that IVIg users have a 42 percent lower risk of contracting Alzheimer’s disease in the five years following treatment. The study, which was funded in part by IVIg manufacturer Baxter International, analyzed a large repository of anonymous health data from SDI Health, including 847 patients who had taken IVIg and 84,700 who had not.

Because IVIg is manufactured by pooling a specific class of antibodies from hundreds of healthy donors, Fillit speculates that it may contain naturally occurring antibodies against harmful amyloid proteins. It may also have a general anti-inflammatory component. But he adds that since the study looked exclusively at patient data, no one can be certain why IVIg has this effect without additional research.

“I think the study provides supportive data for the idea that, by increasing clearance of beta-amyloid from the brains of people with Alzheimer’s disease using antibodies, IVIg may work as a treatment for the disease,” he says. But he also warns that the data is extremely preliminary and should not be used as a justification for taking IVIg, which can cause serious side effects and is extremely expensive.

The antibody angle also offers perhaps the strongest chance for a street-ready Alzheimer’s drug in the near future. Elan Pharmaceuticals is currently running an anti-amyloid antibody treatment, bapineuzumab, through Phase III clinical trials. Phase II data, though, showed only a modest benefit in delaying the disease, and only for a subset of patients. Meanwhile, a clinical trial of an amyloid vaccine, which tries to get the body to make its own anti-amyloid antibodies instead of providing them directly, was halted in 2002 after some patients developed life-threatening encephalitis, a sudden bout of inflammation in the brain.

Innate immunity

Yet another approach is reflected in a July Journal of Alzheimer’s Disease paper, in which scientists studied the potential roles of vitamin D and a form of curcumin—the active ingredient of the Asian spice turmeric—for Alzheimer’s treatment.

Turmeric has long been used as a folk remedy for many disorders, and scientists know it possesses anti-inflammatory properties. In addition, both vitamin D3 and curcumin bind to similar receptors in the body and cause changes in cell signaling that can enhance immune activity.

Instead of looking at its effects on antibodies, however, the researchers studied macrophages, a type of white blood cell. These cells engulf and digest harmful substances in a general manner and are therefore part of what is known as the innate immune system; antibodies, on the other hand, which react only to specific foreign substances and the cells that manufacture them, are considered parts of the adaptive immune system.

The scientists found that a synthetic form of curcumin did enhance the binding of beta-amyloid to macrophages, and that vitamin D showed a similar increase in macrophage activity against amyloid.

“We are the first group to strengthen the innate immune system,” says principal investigator Milan Fiala of the University of California, Los Angeles, Medical School. “The approach of strengthening the adaptive immune system using a vaccine—that led to autoimmune problems. We think our approach is superior.”

But, he adds, both aspects of the immune question need to be solved to offer a potential cure or treatment for Alzheimer’s.  “We think that there are two sides of the immune problem, both a defective clearance of amyloid beta and increased inflammation,” he says. “By improving clearance, we think we will be reducing inflammation. We think these two need to be attacked together.”