In a major advance in the battle against Alzheimer's disease and related forms of dementia, researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center have identified naturally occurring antibodies in human blood that may help defend against the buildup of harmful plaques in the brain.

The newly found antibodies selectively target aggregates of beta amyloid proteins that are toxic to brain cells, while ignoring the benign single-molecule forms of the same proteins. The existence of such antibodies was predicted by animal studies, but they were never previously demonstrated to be present in substantial quantities in blood from normal humans.

Lead researcher Norman Relkin, a behavioral neurologist and neuroscientist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, presented the findings at the second Alzheimer's Association International Conference on Prevention of Dementia, June 11 in Washington, D.C.

Alzheimer's disease affects over 5 million Americans, according to the Alzheimer's Association. The total could climb to 16 million by 2050.

Relkin's team has been testing an antibody-based immunotherapy called intravenous immunoglobulin (IVIg), which is made from the blood of healthy donors, as a potential new treatment for Alzheimer's. Since IVIg was known to contain small amounts of antibodies against beta amyloid, the researchers hoped for a correspondingly modest reduction in the harmful plaques in Alzheimer's patients.

Instead, said Relkin, the lowering effect was more dramatic.

"We couldn't readily explain this based on the low levels of the antibodies known to be present in IVIg," he said. "We suspected there might be another, unseen player."

Studies demonstrated that IVIg initially bound very little single-molecule (monomer) beta amyloid in a test tube. However, it gathered up much more of the protein when the amyloid was aged in a way that allowed clumps of many molecules -- called oligomers -- to form.

These oligomers can grow into the insoluble fibers that cluster around brain cells; a hallmark of Alzheimer's. While monomers are produced from birth and appear to be relatively benign, the oligomers have been implicated as potent toxins responsible for Alzheimer's-linked memory loss and brain cell death. This has led to speculation that they may be the main culprit in Alzheimer's -- and, therefore, a prime target for a new generation of disease-modifying treatments.

To confirm that the antibodies target the toxic oligomers, Relkin and colleagues collaborated with University of California-Irvine researchers Charles Glabe and Rakez Kayed. Using techniques pioneered by Glabe's group, Relkin's team measured and extracted the crucial antibodies from IVIg, demonstrating that these antibodies are present in the blood of normal individuals.

The antibodies seem to distinguish harmful oligomers from benign monomers, researchers say, by detecting differences in the molecules' shapes.

"That was a surprise, because most antibodies work by recognizing some aspect of the chemical structure of their target -- not their shape," said Weill Cornell Medical College (WCMC) molecular biologist and co-author Paul Szabo. "That means that even though beta amyloid monomers and oligomers have the same fundamental chemical makeup, human anti-oligomer antibodies can distinguish between them. The antibodies recognize a particular shape that proteins assume only when they become these toxic aggregates."

That ability may have important implications for immune therapy of other neurological disorders.

"We were able to confirm that the antibodies we found not only recognize oligomers of beta amyloid but also unhealthy forms of other proteins that accumulate in a wide variety of diseases, such as Parkinson's, Lewy body dementia and Prion disease -- the human form of mad cow disease -- to name a few," said Relkin.

While the findings look hopeful, researchers caution that many more studies are needed to determine the safety and efficacy of IVIg as a potential treatment for Alzheimer's.

The work was funded by grants from Baxter Healthcare, the Citigroup Foundation and private philanthropy.