Discoveries bolster hope of blocking Alzheimer's progress

WASHINGTON - A new theory about what goes wrong in the brains of people with Alzheimer's disease is emerging from the laboratories of a handful of researchers in the U.S. and elsewhere.

The concept is a major refinement of the beta-amyloid theory of Alzheimer's that developed in the 1980s and `90s.

If it is correct, it could mean that immunotherapy and the use of specific antibodies that target beta-amyloid protein in an earlier stage of its formation may be the most effective way to attack the disease, which now affects 5.1 million Americans, a number that is projected to reach 7.7 million by 2030.

Such drugs hold the promise to alter the disease process rather than just treating symptoms.

More important, the research suggests that the pathology that causes Alzheimer's might be reversible, at least if it is interrupted at an early enough stage.

These early stage beta-amyloid toxins are known as oligomers.

Research suggests that oligomers play a sinister role in the cognitive process, making it impossible for people to form new memories.

"It's like a hormone from the dark side that blocks the biochemistry of memory," said William Klein, a professor of neurobiology and physiology at Northwestern University's Cognitive Neurology and Alzheimer's Disease Center.

What's more, Klein said, oligomers have been implicated in as many as 28 different diseases involving misfolded proteins, including Parkinson's, type 2 diabetes and all of the so-called prion diseases, such as chronic wasting disease and mad cow disease.

The theory got a bit of a boost last month when researchers reported that they had discovered naturally occurring antibodies in human blood that may help defend against Alzheimer's and several other neurodegenerative disorders that cause dementia, suggesting that Alzheimer's may be a type of immune deficiency disorder.

These antibodies selectively target oligomers.

The research was presented last month in Washington at the Alzheimer's Association international conference on the prevention of dementia.

Oligomers are soluble aggregates of beta-amyloid that eventually form the insoluble clumps of beta-amyloid, the so-called fibrils that build up around brain cells and are the hallmark of Alzheimer's disease.

Under an atomic microscope they look like round or spherical globules, rather than the rod shape of fibrils.

For many years these insoluble fibrils have been thought to be what causes brain cells to die.

That remains the conventional theory of what causes Alzheimer's. But now some researchers think it is the oligomers that are toxic.

Whether all of the oligomer research produces a major breakthrough remains a "big if," said Ronald Petersen, director of the Mayo Clinic's Alzheimer's disease center. But the research is credible, he said.

"It's another piece of evidence that immunotherapy may be beneficial," Petersen said. "I think we are on the threshold."

Oligomers have been shown to cause memory loss and also can bind to dendrites, the root-like appendages from brain cells that form synapses with other brain cells, allowing for communication between neurons.

"They (oligomers) disrupt memory at very low concentrations and they can cause brain cell death," said Norman Relkin, director of the memory disorders program at New York-Presbyterian/Weill Cornell Medical Center.

"They float around, whereas fibrils are like grains of sand and are more chemically inert."

Indeed, insoluble fibrils may be the body's way of trying to neutralize oligomers by aggregating them into a less harmful form, he said.

Several years ago, researchers at Northwestern University began studying the neurotoxic effect of oligomers, giving the molecules the name amyloid-beta-derived diffusible ligands, or ADDLs.

ADDLs are pathogenic and disrupt data storage at certain synapses, interfering with memory formation.

Some research suggests that ADDLs are 70 times more abundant in the brains of those with Alzheimer's than in non-diseased brains, said Northwestern's Klein, who is a co-founder and major stockholder in Acumen Pharmaceuticals, which is developing Alzheimer's and memory loss drugs.

What's more, ADDLs show a propensity to attach to the dendrites of neurons in the hippocampus, the part of the brain that is crucial to new memory formation.

In theory, if antibodies can be used to block oligomers, new synapses could be formed and memory restored, Klein said.

"The brain is constantly rebuilding itself," he said.

Several drug companies now are developing anti-oligomer drugs.

Relkin and others are in the early phases of a clinical trial of intravenous immunoglobulin, or IVIg, which contains antibodies to beta-amyloid oligomers and has shown some initial success in treating a small number of Alzheimer's patients.

The study is being funded by Baxter Healthcare Inc., which markets IVIg.

But as an immunotherapy approach to treating Alzheimer's, IVIg is kind of like using a sledge hammer to kill a fly.

The product, which is derived from blood samples from several thousand people, contains all the antibodies made by humans.

It is expensive and must be administered by IV twice a month.

If scientists can isolate specific antibodies in it that effectively target beta-amyloid oligomers, eventually the antibodies could be made in the lab.

There is even talk of genetically engineering cows so that the antibodies are made in milk.

Meanwhile, oral medications that accomplish the same thing as antibodies are being developed, suggesting that a variety of drugs ultimately may be used to treat the disease.

One such drug, Flurizan, now is being tested nationwide, including on about a dozen patients in the Milwaukee area, said Piero Antuono, a professor of neurology and pharmacology at the Medical College of Wisconsin.

It is believed the Flurizan works by inhibiting the formation of toxic oligomers.

Early results show that it slows cognitive decline, Antuono said.

Drug-maker Myriad Pharmaceuticals is funding the trial.

"We are developing a polypharmacy to intervene at diverse points of attack," Antuono said.