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Alzheimer's Disease Health Center

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FAQ: New Alzheimer's Gene

Researcher Answers Questions About the Newly Discovered Alzheimer's Genetic Risk Factor, CALHM1

Do we know anything about what that variant does? continued...

But also, what we found is that these signals lead to the modulation of the so-called APP processing. The APP processing is a very important pathway that leads to the production of the amyloid peptide. The amyloid peptide is a building block of senile plaque. There is a hypothesis right now in the field that amyloid plaque, but also amyloid peptides before they aggregate into plaque, may be the toxic element in the disease.

So basically, we found a link between the genetics of the disease, with this susceptibility factor, and the production of the amyloid peptides, which is very important.

Where do you go from here?

That's a very important question. ... This new work provides better understanding of the pathogenic mechanism leading to the disease. That's very clear. We have identified a new genetic risk factor and we understand now, in some way, how this genetic risk factor contributes to the disease, to the basic mechanisms leading to the disease. And also, we identified a new gene that we call CALHM1 as a potentially important new target for therapy.

From now on, our attention is focusing on understanding how we can manipulate CALHM1 by the use of small-molecule drugs to improve the pathogenic mechanisms that are taking place in the disease.

Would that call for a new type of drug, or are there drugs that you think might have applications that are already available?

I would say yes to both questions. CALHM1 has similarities with known calcium channels; one of them is the so-called NMDA receptor, a very important calcium channel at the synapse -- the communication region between neurons. NMDA ... is also allowing calcium to get inside the neurons and it's critical for memory formation. CALHM1 and NMDA receptor share some similarities, and there are plenty of drugs, including drugs that are prescribed for humans, that modulate the NMDA receptor. We are currently testing these drugs with the hope that some of them may also modulate CALHM1 and may be beneficial for Alzheimer's disease.

But also, we would like to identify specific drugs that will target CALHM1 only and not the NMDA receptor or other calcium channels. And this is in the context of avoiding side effects. We don't want this kind of problem. Calcium channels are all over the body, not only in the brain at the synapses, but also in [the] heart and in other regions of the body. So if you design a drug that's not specific to CALHM1, you may end up with serious side effects in other organs.

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