126 Reasons for Hope in Alzheimer’s

11/08/2017 11:02 am ET

A new report found there are 126 drugs in clinical trials for Alzheimer’s disease, and they are focused on an increasingly diverse array of targets. This is hopeful news for the 5 million Americans living with Alzheimer’s who currently have no treatment options.

Clinical Trials

Clinical trials occur in three phases and are the final stages of a long road. It takes over a decade—and often much longer—to develop a drug that can be given to patients in clinical trials. Drugs that show positive results in all three phases can apply for FDA approval and, if successful, become available by prescription.

So far, no disease-modifying drug for Alzheimer’s has passed these hurdles, but some among the 126 in trials today have a very good chance. Disease-modifying means a drug can slow, stop, or reverse the progression of Alzheimer’s disease. The five drugs available for Alzheimer’s now only address symptoms, not the underlying causes of the disease.

Aging and Alzheimer’s

Those underlying causes have a lot to do with how we age. We know that aging is the greatest risk factor for Alzheimer’s—the older we get the more likely we are to develop it. But what exactly happens when we age that is so harmful to our brains?

Research into aging and our brains has revealed a complex cascade of dysfunction. The problems can involve inflammation, metabolism, proteostasis, oxidation, cellular stress, and epigenetics.

  • Inflammation can both help and harm. It’s part of our normal immune response and helps us ward off infection. But chronic inflammation can damage our neurons (i.e., brain cells). When we are young, inflammation comes on fast and subsides quickly when the threat is over. But as we get older, it takes longer to reset, meaning we stay inflamed even when our bodies are healthy.
  • Metabolism involves how cells get and use energy. Our brains only account for about 2% of body weight, but use 20% of our body’s energy, which comes from glucose. As we age, our ability to process glucose for energy can wane, starving our brain cells. Some of this can stem from dysfunction in our mitochondria, which are the engines that power our cells.
  • Proteins are critical to our survival, as they carry out most functions in our cells. Proteostasis is simply the “quality control” system for our proteins, which is responsible for their correct formation and for recycling them after they are no longer needed. Both sides of this system are more likely to fail as we get older, resulting in an excess of toxic proteins that, in Alzheimer’s, form plaques and tangles.
  • During our lives, we are exposed to things that, over many years, can build up and damage our cells. Free radicals, the sun, pollution—these all contribute to oxidation and cellular stress. As we age, our ability to repair such cellular damage wanes.
  • Sources of stress to our cells can also cause epigenetic changes. Epigenetics is a process that changes how and how much our genes work, much like a dimmer switch. Over years, we can change our epigenetics for the worse, so “bad” genes are turned up and “good” genes are turned down.

Diverse Targets

Understanding the causes of Alzheimer’s gives us targets to treat it. And the 126 potential treatments now in clinical trials for Alzheimer’s have diverse targets. While 30 of the 126 are focused on a single type of toxic protein called beta-amyloid, others are focused on broader aspects of proteostasis. One of these is a drug called nilotinib that is now being tested in a phase 2 trial at Georgetown University. Nilotinib appears to activate the “recycling system” for proteins, which keeps them from accumulating into plaques and tangles.

Another 12 drugs in trials are targeting inflammation. Among them is GC021109, developed by Gliacure in Massachusetts, which aims to promote normal immune function without inducing chronic inflammation. And 19 drugs are targeting neuroprotection and, as the name implies, designed to protect our neurons from multiple sources of stress and damage. Two exciting drugs in this target area are LM11A-31 from PharmatrophiX in San Francisco and Xanamem from Actinogen Medical in Australia.

These are only a few of the promising drugs for Alzheimer’s that are now being tested in clinical trials. In my 30 years as a geriatrician and neuroscientist, I have never been more hopeful than I am today. I believe that the first disease-modifying treatment for Alzheimer’s is only a few years away. And the first success will lead to more approved drugs and a future in which Alzheimer’s is no longer a threat to older people.

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