The email my wife sent me had the subject line of “Fwd: Alzheimer’s Breakthrough”. I didn’t even bother to open that email for a day, because I have seen that type of headline before; such a subject usually mean BS (bad science).
But this one was different. When three different mice models of Alzheimer’s disease were treated with an already FDA-approved drug, given via gavage (pushed down into the stomach of the test mice through a tube), their beta-amyloid plaque melted away. The biggest bad guy in Alzheimer’s is a sticky protein called beta-amyloid. Either too much is made or not enough is cleared away, and as beta-amyloid accumulates on the brain, it creates a gooey clog in the synapse, preventing the neurons that meet there from communicating. As time progresses, we start to see symptoms of Alzheimer’s.
More importantly, the mice had a magnificent return of cognitive function or at least as best as what can be tested in mice. And such was based on a predicted response by the drug in turning on the Apo E gene. As it was an approved drug, we may know very quickly if this works in humans, as we already know the toxicity and way to dose this drug. But let’s go back to the start.
Your brain cells put out waste products or “poop” in the form of beta-amyloid protein. Normally, you have a garbage truck in the form of Apo E that comes along and picks up that poop. If one of the Apo E genes you get is a mutant or dysfunctional, your risk of Alzheimer’s disease goes up about 30%. If you have two, it goes up more than 60%. Lack of function of this gene leads to the human form of Alzheimer’s disease. That is how these mice were created – they were literally designed to produce lots of beta-amyloid. The net result in these three strains of mice is inflammation in areas of the brain with beta-amyloid, with subsequent neuron or brain cell destruction, and progress to Alzheimer’s disease.
Case investigators gave this drug to express – or turn on – the Apo E gene and make it more active. You can think of it as putting more garbage trucks in your brain to pick up more of the beta-amyloid waste product; thus, less beta-amyloid remains in your brain to stimulate inflammation, and consequently, less brain cell destruction. With the group at Case Western Reserve (and the study was done at the lead institution of Case Western Reserve but also involved the University of Pennsylvania and Washington in St. Louis, three not-so-shabby institutions), they noted that 25% of the beta-amyloid disappeared in 6 hours!!! And 75% of it in 3 days. If you extrapolate that to human studies, that would be the same thing as 75% of that plaque disappearing in 100 human days.
But more importantly, brain cognition (in mice, the ability to have nesting behavior and the ability to sense smells) returned quickly, and special memory reappeared in 20 days.
Okay, so, what is the hold up in trying this in humans? Actually very little. The hold up would be identifying the side effects of this drug and whether there is enough of the drug available. The drug is Bexarotene, made by a small company, for a specific cancer diagnosis. It does cause liver, thyroid and blood cell problems in some people, birth defects, kidney failure and some other not so pleasant things. Obviously, you don’t have to worry about birth defects as most Alzheimer’s patients are past their procreating years.
I was so encouraged by this study that I immediately interviewed Paige Cramer, a PhD candidate from Case Western Reserve and the lead author on the study. She said her lab had been trying approaches to turn on the Apo E gene, and she was lucky enough to decide to try this one. I immediately emailed four other experts in the world in Alzheimer’s disease that I know, and 3 of the 4 who responded in a day all were enthusiastic about this. Perhaps none more so than Jeff Cummings, MD, PhD, the lead doc and scientist at the Cleveland Clinic Lou Ruvo Center for Neurodegenerative Disease in Las Vegas. He commented that though this was incredibly promising and that the studies could be done relatively quickly, because the toxicity and properties of the drug are known, there are many examples of removing amyloid in mice that failed to transfer to human benefit.
Alzheimer’s affected about 5 million people in 2010 in the US, and is predicted to increase to more than 12 million in 2050, with a worldwide prevalence going from about 25 million cases now to over 100 million in 2050. The cost in the United States for caring for such patients will increase from $170 million now to over a trillion in 2050 (not counting the time value for 30 million family caregivers expected in 2050).
This drug could be as radical a breakthrough in this area as was the polio vaccine in wiping out polio for us who lived through Elvis’ greatest contribution in the 1950s. When Elvis volunteered to get a vaccine for polio on TV and for newspaper publication, less than half of 1% of Americans had gotten vaccinated against polio. Within 6 months of his getting vaccinated on TV and with the picture on the front page of 66 major newspapers, more than 80% of Americans had been vaccinated against polio.
So, what remains for human testing? Well, if this is really as dramatic in humans as it is in the mice, a study probably needs to have 30 people in three groups – one that would receive a low dose of Bexarotene, another that would receive a high dose of Bexarotene and a placebo group. Alzheimer’s disease has a variable prognosis and a variable time frame, so for the study to get results, you would have to see a major difference in their prognosis over a 6-month period; people with fairly severe Alzheimers disease would be enrolled (the average time from diagnosis of Alzheimer’s disease to death from it is about 12 years). These volunteers would be studied with PET scans to look at plaque size, but, more importantly, repeated neuro-cognitive testing on each group over the 6-month period. One would hope to see a dramatic improvement in even the low-dose group. Possible side effects would have to be monitored.
Would the FDA stop this study because Bexarotene isn’t approved for this? I doubt it. A study like this would simply need IRB (Institutional Review Board) approval at the institution doing this test. An interested Alzheimer’s family support group would push such, and the population of patients we have in the Cleveland Clinic Lou Ruvo Center for neurodegenerative disease in Las Vegas or several other centers would likely have 90 such patients.
We understand the lead investigators at Case Western Reserve have formed a corporation with a patent for this use of Bexarotene. They should be the direct beneficiaries, and this process will probably proceed quickly. After all, this is an already-approved drug. It is a new use, but it is approved so its safety profile is available.
If you pick patients in a very advanced stage of the disease, many family members and patients would want this study, as there is little hope of other therapies coming along in the meantime. Of course, brain destruction might have progressed too much in this group, and this therapy might only be effective in earlier stages of the disease. Science is rarely simple. And always much more expensive than you wish.
But my prayer is that Paige Cramer is lucky enough to win the lottery, because like Elvis, it may be better to be lucky and skilled than just skilled. And, of course like Elvis, I hope she wipes out a horrible disease.