Dementia of the Alzheimer Type

Toronto Team Uncovers Alzheimer's Gene

By Susan Jeffrey
The Medical Post, July 4 1995

Gene discovery seen as new piece in the Alzheimer's puzzle

TORONTO - A gene associated with familial Alzheimer's disease (FAD) has been found by University of Toronto researchers. They have identified five mutations of the gene, located on chromosome 14, in seven pedigrees with FAD from all over the world. The presence of these mutations confers an almost 100% risk of developing AD. While the familial form of the disease accounts for only a fraction of the Alzheimer's population, the importance of this discovery lies in its potential to illuminate the mechanism behind the swift mental deterioration, said Dr. Peter St. George-Hyslop, who led the Toronto research group. "This particular type of Alzheimer's disease is the most aggressive form, with an early age of onset and a relatively rapid progression, but it is otherwise identical to all other forms in terms of pathology and clinical dementia," said Dr. St. George-Hyslop, assistant professor in the department of medicine, division of neurology at the University of Toronto.

The function of this gene may be altered by a mutation in those with familial AD, but in the wider population the function may be deranged by other factors. This in turn may alter its relationship to the amyloid precursor protein gene, or the apolipoprotein E gene, known already to be associated with other forms of AD.

But because the clinical course associated with this gene is very severe, he added, the gene product may serve a critical function in protecting against the disease. Their early investigation suggests it may be an integral membrane protein, he said, but which membrane isn't clear.

"The greatest significance of this observation is that it's a new piece in the puzzle which, put it into the context of all the other things we know, brings us closer to a clearer idea of the biochemistry of the disease and a more rational approach to treatment," said Dr. St. George-Hyslop in an interview.

"This is a substantial advance in our understanding of familial Alzheimer's disease," said Dr. Dennis Selkoe, professor of neurology at Harvard Medical School, in an interview. Dr. Selkoe, himself a prominent Alzheimer's researcher, wrote an editorial accompanying publication of the report in the journal Nature.

"It's the most malignant form of the disease, so we were all waiting in the field to know what the nature of it is," he said. "It's a very exciting development."

The paper lists 33 authors from 14 centres in Canada, the United States, Japan, Italy and France. At least one of the seven pedigrees come from each of these five countries.

Their finding makes three genetic loci now associated with AD. The E4 allele of the apolipoprotein E gene on chromosome 19 is associated with a large proportion of late onset disease, where symptoms appear after 60 years of age.

Mutations in the gene for beta amyloid precursor protein have been found in families with disease onset before 65. Onset in the most severe form associated with the new gene can appear as early as age 30.

"Peter's discovery is one of the half dozen most important in the field of Alzheimer's disease this century," said Dr. Daniel Pollen, professor of neurology at the University of Massachusetts, Worcester, and a co-author on the paper.

"This is comparable to the cystic fibrosis gene out of the same medical centre a few years ago," he added. "Canada can be extremely proud of what the Toronto group did."

Until now, all the mechanisms investigated have been related either directly or closely to beta amyloid, found in the characteristic amyloid plaques in Alzheimer brains, Dr. Pollen said. "This is the first mechanism that clearly is something different, and it's an entirely fresh crack at the problem," he said.

Dr. Pollen's role in this research was to examine members of two of the study pedigrees to ascertain the presence or absence of clinical disease. One of the families are descendants of Hannah, the first case of the disease described by Alois Alzheimer.

The most significant aspect for members of these families is they can now be tested and know with virtually 100% accuracy whether or not they face AD, Dr. Pollen said. Like families with Huntington's disease, their dilemma is whether they want to know.

"All in the family I study have decided they don't want to know, but part of it is optimistic," he said. "They feel that if we've gotten this far in the 40 years or so since Watson and Krick first came up with the structure DNA, that in the next 40 years, maybe there'll be a treatment."

For those considering children, "They have confidence, they have hope and a real belief that there'll be some treatment by the time their baby might be at risk," Dr. Pollen said.

Copyright 1995 Maclean Hunter Publishing Limited
Reprinted with permission.

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