Dennis Selkoe on the Amyloid Hypothesis of Alzheimer's Disease
Special Topic of Alzheimer's Disease Interview, MARCH 2011
There's another enzyme, beta secretase, that cuts APP first. Then, presenilin (aka gamma secretase) cuts the remaining piece of APP to release the amyloid beta protein. Imagine you have a piece of string and you want to release a smaller piece from the middle—you need to cut it twice. If the original string (i.e., APP) is like the alphabet, running from a to z, then you cut first at m and later at q, and you get a little piece that goes from m to q. Well, one cut in APP is made by gamma secretase (at q) and the other is made first by beta secretase (at m). This gamma secretase enzyme is now called the presenilin/gamma secretase complex, and it's just as important as we thought it was eight years ago.
You can't get Alzheimer's without presenilin cutting APP. The presenilin gene and its protein turn out to be necessary to get Alzheimer's. And it turns out that though it was discovered through the study of AD, presenilin is relevant to many, many other normal biological events and even to other diseases. This is because presenilin/gamma secretase has more than a hundred different substrates, which are proteins that it cuts. Only one of them is APP.
Why do you think there's been so little progress, if any, in developing a drug that can slow the progression of Alzheimer's?
That's a crucial question, and I think about it all the time. I'm actually working toward the improvement of clinical trials and how to analyze them in Alzheimer's that will help address this. My opinion is that the drugs that have been tested so far were highly flawed.
Let me give a very concrete example: Eli Lilly had one of the biggest disappointments in Alzheimer's treatment when it stopped a phase III trial of a new drug last September. Their drug was a gamma secretase inhibitor, which is just what I've been saying I'd like to see. But it was not a good drug. It inhibited presenilin/gamma secretase from cutting many, many different proteins—other proteins—and one in particular is called Notch, which is a very famous molecule in biology. It's very important in fruit flies, worms, humans. It controls aspects of cell fate; how one cell becomes one thing and another cell becomes something else entirely. And you don't want to mess with that, even in adult humans, where it's important in the gastrointestinal tract and bone marrow. For example, to make the proper cell in the gut that makes acid, we need Notch.
Now, Lilly's drug had what we call a therapeutic index of 3. That means the dose of the drug that does the good thing—blocking the cutting of the APP by presenilin to lower amyloid beta—is one-third that of the dose needed for doing a bad thing—inhibiting the cutting of Notch. At first glance, that might not seem so bad; you need three times the active dose before you block Notch. But it still isn't a good therapeutic index, and frankly a number of scientists in the field said in advance that it doesn't look like a good drug to test. God forbid it doesn't work; it will set back the field. People will become disillusioned. Or God forbid the patients get sick.
"My hypothesis, and I haven't written this widely, is that amyloid beta protein does not bind to a particular protein receptor on cells."
Well, Lilly announced in September that the patients didn't get better and they stopped the trial short and said some people in the trial had clear signs of Notch toxicity, for example, developing a type of skin cancer. This is not a minor manner. And they had other problems—gastrointestinal problems, etc. Lilly also said, by the way, when they cognitively tested patients during the trial, they actually seemed to do worse on the drug rather than better.
So what did that say about the amyloid hypothesis itself? You certainly don't seem to have lost faith in it.
People uncomfortable with the amyloid hypothesis said they knew this would happen: amyloid is the wrong target. You don't want to lower it. But the fact of the matter is that it's far more likely that the multiple side effects the patients experienced with Lilly's drug led to somewhat poorer cognition while they were on the drug.
When my patients with Alzheimer's disease get urinary tract infections, which they do, their dementia seems to be much worse. They get more confused because they can't tell you that it hurts a little bit when they have to go the bathroom, and they have to go a lot. Their children call me and say "suddenly, my mom is just different." I say take them down to the doctor and get a urine culture, and when they take care of the urinary tract infection the dementia improves again.
And my point is that in Lilly's trial, they probably caused enough side effects by inhibiting the cutting of Notch protein and, indeed, other proteins also, so there was a price to pay. Patients got more confused. If I'm right about that, then when they follow these patients longer and the Notch side effects clear up without the drug, they should go back almost to their baseline cognition, or perhaps just a little worse, given the time that has passed.
Are you discouraged by the progress that's been made, particularly after the failure of this Lilly drug?
This Lilly drug is now the most common failure cited as evidence that the Alzheimer's field is in a state of malaise, that it's really in trouble and we may not know what we're doing. I don't think that's right at all. We're moving right along with experimental treatments. There are about 60 or so trials ongoing for Alzheimer's drugs worldwide, some in phase I, some in phase II, some in phase III.
The problem is that the first three drugs that were tried in large trials were all poorly thought out. People, understandably, were anxious to get their companies into drug trials for Alzheimer's disease, and they seemed to have chosen the wrong drug. The other two examples that also failed in phase III, like the Lilly drug, had poor attributes as drugs. They were unlikely to be safe and effective.
To summarize, I believe the field is moving along in a rational manner. Therapeutics are based on what we know about the biology of a disease, and companies and academic researchers are developing agents, doing so on a firm footing—although it's never firm enough—and doing the necessary trials. And I think the current trials are going well enough. Some of these drugs have the chance to be successful, and it means they might really help the patient and we'll know more in the next year or two. But they will only be successful if they are tried in patients with mild Alzheimer's disease, not moderate or advanced, when it appears to be too late to really have an impact.
What would you like to accomplish in the next five years?
I'd like to focus on exactly how the amyloid beta protein first binds to cells and injures them. We don't know how that happens. We know, with all this genetic and biomarker and pathology evidence briefly alluded to above, that amyloid beta protein builds up as you get Alzheimer's, but we don't know exactly how it short-circuits the nerve cells. We have some very exciting experiments underway to figure that out.
"...my opinion is that it's an imbalance of amyloid beta protein in the brain that triggers or precipitates Alzheimer's."
My hypothesis, and I haven't written this widely, is that amyloid beta protein does not bind to a particular protein receptor on cells. I don't think there is a specific receptor for amyloid beta, and certainly not for the amyloid beta doublets and triplets ("oligomers") that appear to be particularly noxious.
Those don't have a natural receptor, and I think instead they bind to a fatty substance on the nerve cell membrane, a lipid. The amyloid beta protein doublet (dimer) is very hydrophobic. It hates water. It has some of its most hydrophobic amino acids sticking out, ready to accept another amyloid beta protein, so that a dimer goes to a trimer and on to a tetramer, etc., and it suggests that amyloid beta protein assemblies will do anything they can to get out of an aqueous environment. They can't tolerate water. So they stick to the very sticky lipid environment, which is the surface of these nerve cells and many other cells in the brain.
Another question that I really would like to understand is how antibodies can be used to prevent or treat Alzheimer's. You're probably aware that advanced trials are underway—they've not yet failed, and I hope, of course, that they won't—of vaccines and antibody treatments for Alzheimer's. I would like to know more about how the latter might benefit the patient.
My colleagues and I wrote a paper in Nature Medicine in 2008, which has been cited a lot, describing, among other things, how certain antibodies can neutralize the bad effects of amyloid beta dimers on nerve cells (Shankar GM, et al., "Amyloid beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory," 14[8]: 837-42, August 2008). The dimers (and other, larger oligomers) can cause interference with synaptic transmission.
I would like to know more about how the antibodies prevent that, because in my biased opinion, the best shot we have now is immunological treatment for amyloid beta, an antibody against amyloid beta, which is currently in a phase III trial in some 25 countries. I would like to know more about how that antibody neutralizes the effects of amyloid beta protein and indeed whether it actually does so in humans.