Suspicious DNA: Chromosome study homes in on Alzheimer’s disease

Like crime suspects yanked from a police lineup and held for additional questioning, several human chromosomes now face intensified scrutiny for possibly harboring genes involved in Alzheimer’s disease. New data from a genome-screening study suggest that portions of at least nine chromosomes may be implicated in the development of the disease.

Inherited traits account for a portion of any person’s risk of Alzheimer’s, says Rudolph E. Tanzi, a neurologist at Massachusetts General Hospital in Boston. About 10 percent of people age 65 or older have the incurable, progressive dementia. Several rare genes that invariably lead to the disease have been identified, but most of the genetic factors in Alzheimer’s remain unknown, Tanzi and other researchers suspect.

Now, several new chromosomal regions that could hide such risk-increasing mutations have been identified. Further, the new data home in on the responsible part of one candidate gene that has already been implicated in Alzheimer’s disease.

In search of telling genetic patterns, Tanzi and his colleagues screened the entire genomes of nearly 2,000 people–1,439 of whom had developed Alzheimer’s after age 50–from 437 Alzheimer’s-affected families.

The researchers scanned each chromosome at short, regular intervals to locate and identify tiny variations in genetic sequences–called single-nucleotide polymorphisms (SNPs)–among the participants. The scientists then searched for statistical associations between particular SNPs and the incidence of the disease.

Tanzi’s team found numerous potential links between certain SNPs or combinations of SNPs and patterns of Alzheimer’s disease incidence. Their results replicated earlier findings that APOE4, a particular mutation on chromosome 19, increases risk of the disease. The new data also support previously suggested associations between the disease and certain regions of chromosomes 1, 4, 9, and 10. In addition, the new study flags at least four other chromosomes–6, 11, 14, and 21–that appear to contain genetic factors influencing Alzheimer’s disease risk.

Most significant about Tanzi’s study is that it identifies new regions of the genome for Alzheimer’s disease research, says Sangram S. Sisodia of the University of Chicago.

While Tanzi and his colleagues are pleased that the new findings will provide fodder for further research, their priorities remain with chromosomes 9 and 10.

After all, their data suggest a link between elevated Alzheimer’s risk and a region of chromosome 10 near a gene called IDE. That gene has been on researchers’ radar screens because it produces an enzyme involved in clearing brain tissue of the peptide called beta-amyloid. This peptide is overabundant in the brains of Alzheimer’s patients and forms plaques that may underlie the dementia.

When analyzed independently, no single SNP along the relevant portion of chromosome 10 showed a significant association with the disease. This suggests that none of the SNPs is likely to contribute directly to Alzheimer’s risk.

However, when Tanzi’s group looked for associations between the disease and certain patterns within a series of tightly spaced SNPs on chromosome 10, they found a pattern at one end of the IDE gene that did register a statistical connection to the disease.

It could be that a mutation responsible for elevated Alzheimer’s risk usually lies hidden among the SNPs that make up that pattern in this stretch of chromosome 10. That pattern could therefore serve as a diagnostic marker for Alzheimer’s risk.

Tanzi presented his team’s results on Feb. 16 in Boston at the annual meeting of the American Association for the Advancement of Science.