New genetic risk for Alzheimer's disease found

A Canadian-led research team has found a gene that may increase the risk of Alzheimer's disease, a discovery theyhope will one day lead to a diagnostic test or perhaps a treatment.

People carrying a mutated version of the gene SORL1 seem to show a modestly increased risk of late-onset Alzheimer's compared to those with the normal version, the researchers say in Sunday's online issue of the journal Nature Genetics.

The mutations were significantly overrepresented inpeople with dementiain the study led by Dr. Peter St. George-Hyslop.If further tests confirm that SORL1 can predict Alzheimer's, it will be the fifth gene linked to the disease.

"The usefulness of it will probably be determined on how good a predictor it is of getting the risk for Alzheimer's disease and whether there's anything that you can do about that risk,"said St. George-Hyslop,director of the Centre for Research in Neurodegenerative Diseases at the University of Toronto.

The researchers also pointed to a potential way that the mutation or variant increases the risk of Alzheimer's, the most common form of dementia in Canada, affecting one in 20 or about 290,000 Canadians over 65.

Preliminary data suggest people with Alzheimer's tend to have lower levels of SORL1 in their blood cells, the team found. The gene produces a protein that helps clear the buildup of chemicals that can damage the brain.

Tracing a neurotoxin

They experimented and found that when they reduced the level of SORL1 in a cell, it promoted the production of toxic A-beta peptide.

This is important because the generation of A-beta peptide is thought to be a key event in the progression of Alzheimer's, which leads to memory impairment, behavioural changes and dementia.

"There may come a time when individuals at risk will be profiled for the multiple genes that contribute to this illness," said Dr. Howard Feldman, head of neurology atthe University of British Columbia in Vancouver.

The findings were confirmed using DNA samples from 6,000 volunteers in four distinct ethnic groups: Caribbean-Hispanics, North Europeans, African-Americans and Israeli-Arabs. Previous studies focused on populations with American and European ancestry.

Complex genetic links

The hallmark of Alzheimer'sis the buildup of amyloid precursor protein, or APP, into plaques in the brain. Researchers suspect that when the protein enters some regions of the brain, cellscan't work and therefore die, leading to disorientation and progressive memory loss.

The gene they found controls the distribution of APP inside nerve cells of the brain. When working normally, SORL1 prevents APP from being degraded into the neurotoxin A-beta.

The researchers said genetic links are complex and it is important to do more studies to see whether the same pattern is found in other ethnic groups with different genetic makeups and lifestyles.

Currently, drug treatments have only a modest effect on the progression of Alzheimer's. The complexity of the brain's many proteins, chemicals, cells and functions means that tinkering with one can have unexpected consequences and potentially serious side-effects.

Researchers say that is why identifying the many genetic pieces of the Alzheimer's puzzle is so important. The discovery of another gene is described as a step toward new therapies.