Gene defect tied to Alzheimer's cases.

Gene defect tied to Alzheimer's cases

British researchers have identified a genetic defect associated with an inherited form of Alzheimer's disease, marking the first link between a gene and the degenerative syndrome. But the inborn error occurs in only a fraction of Alzheimer's cases, and its true role in the disease remains unproven.

A research team led by John Hardy of St. Mary's Hospital Medical School in London discovered the typographical error in the genetic code of a person who had died of early-onset Alzheimer's, an inherited form of the disease that usually strikes during the fourth or fifth decades of life and accounts for less than one-third of all Alzheimer's cases. The defect, located on chromosome 21, causes cells to insert a single incorrect amino acid while manufacturing a substance called amyloid precursor protein. Family members not affected by the disease, and 100 unrelated, normal individuals from the local population, lacked the genetic error.

DNA analysis of 18 individuals with early-onset Alzheimer's in 16 other families revealed two members of one family bearing the same mutation, the researchers report in the Feb. 21 NATURE.

Some researchers have suspected that Alzheimer's results from an inherited or acquired genetic garble that causes cells to produce defective amyloid precursor protein. Breakdown products of the precursor protein appear in large quantities in the brains of Alzheimer's patients, suggesting to these scientists that the disease results from production of an unusually fragile precursor protein.

But until now, all attempts to demonstrate a link between the precursor protein gene and Alzheimer's had proved inconclusive. That left other scientists arguing that amyloid breakdown and deposition represent redherring side-effects of a more fundamental and still unidentified pathological process.

The current study does little to settle the argument, and may strengthen an increasingly popular hypothesis that Alzheimer's has many underlying causes. Moreover, while scientists may find the newly discovered amino acid substitution in some Alzheimer's patients, it remains unclear whether the defect plays a real pathological role or simply tags along with a more critical genetic error.

The researchers caution that some stretches of DNA taken from their Alzheimer's patients remain unexamined, leaving open the possibility that more important mutations lay elsewhere within the amyloid precursor protein gene or in entirely different chromosomal locations. Also unclear is the relevance of the work to the much more common form of Alzheimer's, which strikes individuals late in life.