New lesion found in Alzheimer brains.

In 1906, Alois Alzheimer stood before psychiatrists in Germany and described his studies of a 51-year-old woman who would make his name tragically famous. The woman had had severe memory problems before her death, and when Alzheimer autopsied her brain, he found it riddled with two kinds of lesions: plaques, which are extracellular deposits of a protein fragment now called beta-amyloid, and tangles, intracellular clumps of a protein now known as tau.

These plaques and tangles, observable only in autopsies, currently serve as the only definitive diagnostic markers for Alzheimer's disease, the memory-robbing neurodegenerative disease that afflicts millions of elderly people.

A research group, however, now suggests that Alzheimer missed an equally common brain lesion, as have thousands of scientists since who have examined the brains of people with Alzheimer's disease.

In addition to plaques and tangles, the brains of Alzheimer's patients contain extensive extracellular deposits of a still unnamed protein, Marie L. Schmidt of the University of Pennsylvania School of Medicine in Philadelphia and her colleagues report in the July America Journal of Pathology.

In shape and size, the new lesions, labeled AMY plaques, often resemble the disease's characteristic amyloid plaques, and they almost never appear in brains devoid of the amyloid plaques.

"When you find amyloid, you seem to find AMY nearby," says study coauthor Virginia M.-Y. Lee. Yet the new lesions are distinct from the amyloid plaques, rarely overlapping in the brain, the investigators report.

The discovery of AMY plaques was accidental. Having generated antibodies to the components of tangles, Lee and her colleagues unexpectedly found that four of the antibodies did not recognize tau but instead bound to a protein apparently contaminating the tangles.

The researchers then used one of these antibodies to study brains of people who had had typical Alzheimer's disease. In all 32 brains examined, the antibody revealed AMY plaques. Like amyloid plaques, AMY plaques also appeared in the brains of people who had Down's syndrome. Yet in elderly people without dementia, including those with schizophrenia and other neurological diseases, AMY plaques were rare or absent.

How did AMY plaques remain invisible for nearly a century? Lee notes that the traditional dyes used by pathologists do not highlight these brain lesions.

Researchers hope to quickly purify the protein in AMY plaques and identify the gene encoding it. Lee speculates that mutations in that gene may trigger some Alzheimer's disease, much as mutations in the gene for beta-amyloid's precursor protein can.

Instead of causing brain cell death, however, the AMY plaques may merely appear as a byproduct of the destruction that occurs in the disease. Similar debates about tangles and amyloid plaques still rage on.

"Let's not talk about this as a breakthrough yet," cautions Donald L. Price, a neuropathologist at John Hopkins Medical Institutions in Baltimore.