Why Drugs for Alzheimer’s Are So Hard to Develop


Finding treatments for Alzheimer’s disease is simultaneously one of the most pressing and difficult tasks in medicine today. Between 2000 and 2015, the number of deaths resulting from Alzheimer’s has shot up by 123 percent. Today, around one in 10 people over age 65 have the disease. The drugs available for Alzheimer’s aim to ease symptoms of the disease, but they cannot slow or reverse its progression. The last time a new medication was approved for Alzheimer’s was 15 years ago.

But in recent years, Alzheimer’s drugs in clinical testing have largely failed to produce adequate results. There are, however, a handful of promising options still in the running. David Geldmacher, a neurologist at the University of Alabama at Birmingham, is working on a phase three clinical trial of a drug called aducanumab, which is sponsored by the biotech company Biogen. Medium spoke to Geldmacher about the challenges of drug discovery for Alzheimer’s disease and what keeps him optimistic for the future.

Medium: Why is it so difficult to develop drugs for Alzheimer’s disease?

David Geldmacher: One of the biggest issues in coming up with effective therapies for Alzheimer’s disease is that we really don’t know critical elements [underlying] the mechanism [of the disease] in most people with the illness.

We know 1 or 2 percent of Alzheimer’s cases are clearly inherited. We tend to see, in those individuals, that the illness begins in the mid-forties. Because those mechanisms are so easily understood in the genetically determined cases, that’s what we’ve been able to use in animal models.

A lot of work in Alzheimer’s disease is based in animal models with these human genes that cause Alzheimer’s. And things that worked well in animals have not turned out to work well in people. What we have learned, however, is that the process of Alzheimer’s disease begins in the brain years, probably decades, before the first symptoms emerge. In many cases, we’ve been trying to treat the illness too late in its course.

How is the trial that you’re running different from those that have failed in the past?

What we’ve done in this particular study is use an antibody that has a slightly different configuration that targets a different part of the amyloid [compound] than some of the past treatments have targeted. But, more importantly, we are focusing on the disease very early on, when people have only mild cognitive symptoms. That means there has been less overall damage to the brain, and there’s a greater opportunity to prevent further cell death or rescue cells that have been made sick by the amyloid but not killed by them.

Can you tell us about the findings so far?

The study is underway, so there are no findings that are reportable at this point. In a prior study, which was reported in Nature in 2016, the aducanumab antibody showed that it could clearly reduce the amount of amyloid plaques in the brains of people with Alzheimer’s disease. PET scans were done before treatment was administered and then at the end of treatment. People who received the aducanumab had a reduction in the amyloid burden in their brain. People who received the placebo during the same trial actually had an increased amyloid burden.

This demonstrated that the agent is biologically active on the target we want it to be active on. The other thing noted in that trial was that patients on the highest dose of the medication showed some slowing of the progression of illness. This is one of the first studies where that’s been so clearly evident.

Interestingly, at six months into the study, the doses did not distinguish themselves, so treatment was not clearly different from placebo. But at 12 months, the difference emerged. That tells us that the process by which the antibody is effective is a gradual one.

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