BioEd Online

A US team has identified what could be the earliest indication of Alzheimer's, a discovery that may help to diagnose the disease and perhaps stop it progressing.

Researchers believe that some people show signs of memory loss years before they develop Alzheimer's. But they are not sure what causes these problems, or how they turn into full-blown dementia.

To find out, Karen Ashe at the University of Minnesota, Minneapolis, and her team studied a strain of mice that, like people, develop mild memory problems in middle age before getting more severe Alzheimer's symptoms.

Damaging clusters

The mice were genetically engineered to make a version of a human protein called amyloid-. Researchers know that this protein clogs the brains of Alzheimer's patients late in the disease.

By extracting amyloid- from the animals' brains, the team discovered a knot of 12 proteins that appears outside brain cells just as memory loss occurs. These clusters, which it calls A*56, are different from the large plaques of amyloid- that form later in Alzheimer's patients.

The more of these clusters mice have, the worse their memories are, the team reports in Nature¹. And injecting clusters into the brains of rats causes temporary amnesia.

The tactic of seeking the molecular changes that occur at the very first signs of memory loss is "somewhere between ingenious and lateral thinking", says neuroscientist Richard Morris, who studies memory formation at the University of Edinburgh, UK. Before this, a lot of research focused on the later stages of the disease, when neurons are dying and it is hard to work back to the initial problem.

Brain jam

Ashe proposes that the clusters of amyloid- could interrupt memory by jamming communication between neurons. She suggests that they could be one cause of the mild memory loss widely associated with old age.

They could also prefigure the death of neurons and severe cognitive problems. "This may be the seed that defines who gets Alzheimer's," she says.

The study adds to evidence that Alzheimer's starts out when molecules of amyloid- start to clump together. "These are the bad guys," says Alzheimer's specialist Dennis Selkoe of Brigham and Women's Hospital in Boston, Massachusetts.

The idea needs testing with additional experiments, Ashe says. She is scrutinizing the preserved brains of people who displayed early signs of Alzheimer's and then died from other causes, to see whether they contain A*56.

Another key test is whether drugs that stop the protein clusters forming can halt memory loss in mice. "That's the gold-standard proof of this hypothesis," Ashe says.

Early warning

Alzheimer's is difficult to diagnose and incurable; there are an estimated 18 million sufferers worldwide.

Spotting clusters of amyloid-b in the blood might help doctors to identify who is at risk of disease, helping them to target possible treatments. Drugs or vaccines that stop the clusters forming might block the brain's decline.

Researchers are already testing several methods to block the production or accumulation of amyloid- in humans. "We're in good shape in what needs to be done therapeutically," Selkoe says.

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