Researchers have discovered the second, strong genetic risk factor for developing late-onset Alzheimer's disease, according to a new report in the June 27th issue of the journal Cell, a Cell Press publication.
The newly discovered gene, which previously had no known function, is predominantly active in a region of the brain that is hit early in the disease, where it acts as a channel for calcium, they show. Called calcium homeostasis modulator 1 (CALHM1), their evidence shows that different variants of the gene also influence the levels of amyloid-ß peptides. Those peptides make up the plaques that form in the brains of those with Alzheimer's.
"We are very excited about the idea that CALHM1 could be an important target for anti-amyloid therapy in Alzheimer's disease," said Philippe Marambaud of The Feinstein Institute for Medical Research and Albert Einstein College of Medicine. CALHM1's presence at the cell surface should ease the process of drug design, he explained. And because its activity is restricted to the brain, drugs aimed at CALHM1 are less likely to have peripheral side effects.
The possibility for side effects is a "big question mark" for other drugs now under clinical study, Marambaud said. Those drugs primarily target enzymes responsible for producing amyloid-ß peptides, he noted, but those enzymes are also found in other parts of the body.
The new findings come just as another group has reported the identification of an imbalance of calcium in early-onset Alzheimer's disease, linked to a calcium release ion channel. Those results appear in the June 26th issue of Neuron, also a Cell Press publication.
Alzheimer's disease is a progressive neurodegenerative disorder characterized by a massive loss of neurons in several brain regions and by the presence of amyloid-ß plaques. While the rarer, early-onset form of the disease has been tied to a few dominant mutations, the vast majority of late-onset cases are thought to result from complex interactions among different genetic variants and environmental factors.
Previously, the only susceptibility gene unambiguously demonstrated worldwide is a particular variant of the gene known as APOE, found on chromosome 19. Other evidence suggested a second gene could be found on chromosome 10. However, despite intensive research efforts to characterize the genetic factor or factors located, no gene within the chromosome 10 region had been conclusively linked to late-onset Alzheimer's risk, Marambaud said.
Marambaud's team suspected that susceptibility to late-onset Alzheimer's disease might stem from genes active primarily in affected brain regions, such as the hippocampus. Following that logic in the new study, the researchers screened for genes expressed predominantly in the hippocampus that also fell within the Alzheimer's-linked chromosomal region.