An international group of scientists found that a new gene called calcium homeostasis modulator 1 (CALHM1), with a previously unknown function, is linked to late-onset Alzheimer’s Disease making this the second discovery of a strong genetic risk factor for the disease.

The study was the work of researchers from the US, France, Italy, UK, and Australia, led by Dr Philippe Marambaud of The Feinstein Institute for Medical Research, Manhasset, New York, and Albert Einstein College of Medicine, Bronx, New York, and is published online in the June 27 issue of the journal Cell.

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by the build up of senile plaques made of amyloid-beta peptides and a massive loss of neurons or brain cells.

The early-onset form of Alzheimer’s is thought to be linked to a few dominant gene mutations, but the vast majority of late-onset cases are believed to stem from complex interactions of genes and environment factors.

The study reports that CALHM1 is active mostly in a calcium channel in part of the brain that is affected early in the development of Alzheimer’s. The researchers discovered that variants of CALHM1 influence levels of calcium, amyloid-beta peptides, and susceptibility to the disease.

This study coincides with the publication of another paper in the 26th June issue of a sister journal Neuron, where scientists report finding an imbalance of calcium in early-onset Alzheimer’s Disease that is linked to a calcium release ion channel.

Marambaud said in a statement that:

“We are very excited about the idea that CALHM1 could be an important target for anti-amyloid therapy in Alzheimer’s disease.”

He said because CALHM1 is restricted to the brain, drugs that target it would most likely have fewer side effects, which is a big question mark with drugs that are currently being trialled because these target enzymes involved in production of amyloid-beta peptides, and these enzymes are also present in other parts of the body.

The first gene that was discovered to have a direct link with higher risk of Alzheimer’s Disease was a variant of a gene called APOE, located on chromosome 19. A second gene was thought to be located on chromosome 10, but this proved to be elusive to scientists.

For this study Marambaud and colleagues followed a different kind of hunch, they decided to look for genes primarily active in the brain regions affected by late-onset Alzheimer’s disease, such as the hippocampus. So they screened for genes that met two criteria: they had to be particularly active in the hippocampus and also fall within the likely chromosome regions linked to Alzheimer’s.

So that is how they came across the little known CALHM1. Furthermore they discovered that a variant of this gene occurs more frequently in people with Alzheimer’s than people without the disease. As Marambaud explained:

” 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,” he added.

A single copy of the variant of CALHM1, which causes the amino acid proline to change to leucine and is called p86L because the part of the gene that is responsible for it occurs at codon 86, increases a person’s chance of getting late-onset Alzheimer’s disease by 44 per cent. Having two copies of the variant would increase the risk even further, said Marambaud.

They eventually found that CALHM1 is a calcium channel that controls how calcium gets into cells. They also found that the gene variant that was found more often in people with Alzheimer’s upset the regulation of how calcium gets into cells and increases amyloid-beta levels.

For some time scientists have believed Alzheimer’s is caused by an upset in calcium regulation, but there had been no proof. This study takes a significant step in the direction of establishing the proof, as the researchers wrote in their conclusions:

“The present work provides strong support for the calcium hypothesis of Alzheimer’s disease and is also an important step toward understanding the potential pathological cross talk between calcium signaling disturbances and pathways of amyloid-beta accumulation.”

“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,” they added.

“A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer’s Disease Risk.”
Ute Dreses-Werringloer, Jean-Charles Lambert, Valérie Vingtdeux, Haitian Zhao, Horia Vais, Adam Siebert, Ankit Jain, Jeremy Koppel, Anne Rovelet-Lecrux, Didier Hannequin, Florence Pasquier, Daniela Galimberti, Elio Scarpini, David Mann, Corinne Lendon, Dominique Campion, Philippe Amouyel, Peter Davies, J. Kevin Foskett, Fabien Campagne, and Philippe Marambaud .
Cell, 133, 1149-1161, 27th June 2008.

Click here for Article (PDF).

Sources: Journal abstract, Cell Press statement.

Written by: Catharine Paddock, PhD