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FAQ: New Alzheimer's Gene

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

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.

What would you say to people who think, "If there is this genetic risk factor, should I get a genetic test?"

I wouldn't rush to this right now. It's like the ethical issues related to ApoE4 testing. Is it too early or not? I would say yes. There is no preventive or curative treatment right now for Alzheimer's disease. There are some drugs that are working great, but they don't cure the disease. The idea to have a diagnostic [genetic test] today may not help too much.

But in the future, definitely, when we will understand the whole susceptibility for the disease, definitely CALHM1 [and] ApoE4 should be included and should be considered very seriously when we want to have a comprehensive diagnostic [genetic test] for people.

Besides CALHM1 and ApoE4, how many other genes do you think affect Alzheimer's risk?

There are, I would say, 20 genes -- 20 risk factors -- that show significance in increasing the risk of developing the disease. So ApoE4 and CALHM1 are not the only ones, but they are the most robust at this point.

But these numbers are changing every day because the more populations are added to the screenings, the more information we get on the exact number for the susceptibility genes. Some susceptibilities may be more specific to [certain ethnic groups], so this has to be carefully analyzed and combined.

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