Scientists have now identified a second genetic risk factor for Alzheimer's disease which, until recently, was attributed to the mutation in a single gene. This second gene, called calcium homeostasis modulator 1 (CALHM1), is responsible for the late-onset of this neurodegenerative disorder.
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-B 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.
The researchers have shown that CALHM1, which previously had no known function, is predominantly active in a region of the brain, called hippocampus that is hit early in the disease, where it acts as a channel for calcium. Also, the study cited that different variants of the gene also influence the levels of amyloid-B 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.
He said that CALHM1's presence at the cell surface may make it easy to design drug. And as its activity is restricted to the brain, drugs aimed at CALHM1 are less likely to have peripheral side effects.
Earlier, the only susceptibility gene unambiguously demonstrated worldwide is a particular variant of the gene known as APOE, found on chromosome 19. And other evidence suggested a second gene could be found on chromosome 10.
The researchers thought that susceptibility to late-onset Alzheimer's disease might stem from genes active primarily in affected brain regions, such as the hippocampus. Based on this logic, the researchers screened for genes expressed predominantly in the hippocampus that also fell within the Alzheimer's-linked chromosomal region.
This took them to CALHM1, a gene of unknown function and they discovered that a variant of CALHM1 is found more frequently in people with Alzheimer's disease than in those without.
They estimate that a single copy of that variant, which results in a proline-to-leucine amino acid substitution (designated as p86L because it occurs at codon 86), increases one's chance of getting late-onset Alzheimer's disease by 1.44-fold. Marambaud said that the risk for those with two copies of the p86L variant would be higher still,.
"We quickly found that this variant was associated with the disease. The problem was it was a variant in a gene with no known function. We had no idea what it was," said Marambaud.
On further research it was found that CALHM1 is a calcium channel. They also found evidence that the CALHM1 variant more often found in those with Alzheimer's disease increases amyloid-B levels by interfering with the passage of calcium into cells.
"Moreover, the identification of CALHM1 as a key modulator of calcium homeostasis will allow us to further dissect the precise mechanism by which cytosolic calcium modulates amyloid precursor protein metabolism," concluded the researchers.
The study is published in the latest issue of the journal Cell, a Cell Press publication.