Support the news

What Happens Early In The Brains Of People Who Get Alzheimer's Late?

Alexis McKenzie, right, executive director of The Methodist Home of the District of Columbia Forest Side, an Alzheimer’s assisted-living facility, puts her hand on the arm of resident Catherine Peake, in Washington, Feb. 6, 2012. (Charles Dharapak/AP)
Alexis McKenzie, right, executive director of The Methodist Home of the District of Columbia Forest Side, an Alzheimer’s assisted-living facility, puts her hand on the arm of resident Catherine Peake, in Washington, Feb. 6, 2012. (Charles Dharapak/AP)

As we reported on Here & Now, this week brought news of a promising advance on Alzheimer's disease: A study in the journal Nature that helps illuminate what goes wrong early on in the brains of people who get late-onset Alzheimer's, the most common form. The researchers aimed to connect the dots between the gene APOE4, the strongest known genetic risk factor, and development of the actual disease.

Please read the Here & Now report for more detail, but for the bigger picture, here are some clear insights from Dr. Robert C. Green, a medical geneticist at Brigham and Women’s Hospital and Harvard Medical School. (To sum up in an adjective: Here & Now host Robin Young asked me if this was "great" news on Alzheimer's; I only felt comfortable going as far as "promising." Dr. Green takes it all the way to "exciting.") His points:

It's the kind of breakthrough we need to help us be smarter about the drugs that we take to multi-million-dollar clinical trials.

"What I think is the really exciting part of it is that, for nearly 20 years, we've known that APOE was a robust risk factor for Alzheimer's disease, but we really didn't  know why. And this paper is actually the first paper that begins to offer an answer as to why APOE4 is a risk factor at a molecular level.

The way they did it is quite remarkable: They did it with gene expression profiles, a hot new area, and they found that certain genes were turned up or down by the APOE4,  and they were genes that appeared to regulate the production of the bad amyloid protein associated with Alzheimer’s disease. So the APOE4 didn't directly influence the production of the amyloids; it seemed to regulate up or down these signaling genes, sort of like a cascade effect, to regulate some of the amyloid up and down.

But they didn't stop there. What made it an amazing paper is that they didn't just look at the gene expression studies. They then took it into a mouse model, and took it into cell culture and explored it in cell culture. And then they actually went and looked into some publicly available databases, and they tied it in with genes that had been independently discovered for early-onset Alzheimer’s disease. And they also tied it in with amyloid imaging of Alzheimer's disease. They really did a lot in this paper.

They basically found, with these gene expression profiles in people who had the bad APOE4 variants but were cognitively normal, that they looked very similar to affected Alzheimer's patients, but they did not look like unaffected older patients. So it was a different gene profile than the one associated with just aging.

One of the questions they seemed really intent on answering was, when you look at a patient with Alzheimer's disease, and you see molecular changes, you don't know whether it's causal or a result of the disease. And by finding the same patterns in APOE4 individuals who were unaffected, whose brains had not developed Alzheimer's disease, they were able to make a much stronger argument that the molecular changes they were findings were part of a causal pathway. That's really exciting, it's very elegant science.

It's very good for two reasons:

One is that it continues to support the amyloid hypothesis, which has come under some fire because of some failed clinical trials, and it suggests we are on the right track as we are exploring amyloid. It also starts to uncover previously unrecognized regulatory mechanisms and that gives us new druggable targets.

The concept is very exciting, that you can find drugs that influence these regulators. This is not a treatment that's going to give us a treatment in a year, but I believe it's the kind of breakthrough we need to help us be smarter about the drugs that we take to multi-million-dollar clinical trials. Every one of these clinical trials is over $100 million, so you’ve got to gamble on these drugs, and the smarter we can get about choosing the ones we gamble on, the better we'll use our resources.

This program aired on July 26, 2013. The audio for this program is not available.

Carey Goldberg Twitter Editor, CommonHealth
Carey Goldberg is the editor of WBUR's CommonHealth blog.

More…

+Join the discussion
TwitterfacebookEmail

Support the news