In the News: Lack Of Deep Sleep May Set The Stage For Alzheimer's

Jeffrey Iliff (right) and Bill Rooney, brain scientists at Oregon Health & Science University, look over an MRI. The school has an especially sensitive MRI unit that should be able to detect precisely when during sleep the brain is being cleansed of toxins.

There's growing evidence that a lack of sleep can leave the brain vulnerable to Alzheimer's disease.

"Changes in sleep habits may actually be setting the stage" for dementia, says Jeffrey Iliff, a brain scientist at Oregon Health & Science University in Portland.

The brain appears to clear out toxins linked to Alzheimer's during sleep, Iliff explains. And, at least among research animals that don't get enough solid shut-eye, those toxins can build up and damage the brain.

Iliff and other scientists at OHSU are about to launch a study of people that should clarify the link between sleep problems and Alzheimer's disease in humans.

It has been clear for decades that there is some sort of link. Sleep disorders are very common among people with Alzheimer's disease.

For a long time, researchers thought this was simply because the disease was "taking out the centers of the brain that are responsible for regulating sleep," Iliff says. But two recent discoveries have suggested the relationship may be more complicated.

The first finding emerged in 2009, when researchers at Washington University in St. Louis showed that the sticky amyloid plaques associated with Alzheimer's develop more quickly in the brains of sleep-deprived mice.

Then, in 2013, Iliff was a member of a team that discovered how a lack of sleep could be speeding the development of those Alzheimer's plaques: A remarkable cleansing process takes place in the brain during deep sleep, at least in animals.

What happens, Iliff says, is "the fluid that's normally on the outside of the brain, cerebrospinal fluid — it's a clean, clear fluid — it actually begins to recirculate back into and through the brain along the outsides of blood vessels."

This process, via what's known as the glymphatic system, allows the brain to clear out toxins, including the toxins that form Alzheimer's plaques, Iliff says.

Scientists watch dye flow through the brain of a sleeping mouse.Nedergaard Lab, University of Rochester Medical Center.

"That suggests at least one possible way that disruption in sleep may predispose toward Alzheimer's disease," he says.

To know for sure, though, researchers will have to study this cleansing process in people, which won't be easy.

Iliff studied the glymphatic system in living mice by looking through a window created in the skull. The system also involved a powerful laser and state-of-the-art microscope.

With people, "we have to find a way to see the same sort of function, but in a way that is going to be reasonably noninvasive and safe," he says.

The solution may involve one of the world's most powerful magnetic resonance imaging machines, which sits in a basement at OHSU. The MRI unit is so sensitive, it should be able to detect changes that indicate precisely when the glymphatic system gets switched on in a person's brain, says Bill Rooney, who directs the university's Advanced Imaging Research Center.

When humans enter deep sleep, and toxin removal begins, there should be a particular change in the signal coming from certain salt molecules. That would indicate that fluid has begun moving freely through the brain.

In young, healthy brains, the signal should be "robust," Rooney says, indicating that the toxin removal system is working well. In the brains of older people, and those who are likely to develop Alzheimer's, the signal should be weaker.

Rooney and Iliff have received funding from the Paul G. Allen Foundation to test their approach. They hope to begin scanning the brains of participants within a year.

One challenge, though, will be finding people able to fall asleep in the cramped and noisy tunnel of the magnetic resonance machine.

"It's a tricky thing because it's a small space," Rooney says. "But we'll make people as comfortable as possible, and we'll just follow them as they go through these natural stages of sleep."

If Rooney and Iliff are right, the experiment will greatly strengthen the argument that a lack of sleep can lead to Alzheimer's disease. It might also provide a way to identify people whose health is at risk because they aren't getting enough deep sleep, and it could pave the way to new treatments.

"It could be anything from having people exercise more regularly, or new drugs," Rooney says. "A lot of the sleep aids don't particularly focus on driving people to deep sleep stages."

In the News: Devices, Not Drugs: A Memory Chip for the Brain?

Brain Implant Could Help Patients Generate New Memories

by Christopher York

A team of scientists at the University of Southern California believe they are two years away from creating a brain implant capable of generating memories within patients' brains.

The implications could be profound for medicine -- and probably not horrific in a 'Total Recall' sort of way.

If successful it could help victims of brain injuries and possibly Alzheimer's with memory recall -- and has the potential to help patients remember who they are.

The implant will target the hippocampus, an area thought to be crucial in forming long-term memories.

The team intend to develop a technique to recreate the electrical signals used in the hippocampus that have been lost due to illness or injury.

They have already had success in tests on rats and monkeys.

Professor Ted Berger who worked on the project told MIT Technology Review: "We're not putting individual memories back into the brain. We're putting in the capacity to generate memories.

"I never thought I'd see this in my lifetime. I might not benefit from it myself but my kids will."

How A Failed Alzheimer's Drug Illustrates The Drug Industry's Gambling Problem

by Michael Waldholz Forbes Contributor
 
On Monday, Pfizer, Johnson & Johnson, and Elan Pharmaceuticals announced that the Alzheimer’s drug they were developing together had yielded such a bad result in a clinical trial that they were stopping all further work on it – dashing hopes for the 5 million Americans suffering from Alzheimer’s and becoming the latest piece of evidence of the drug industry’s strange gambling problem.

Wall Street expectations weren’t high, with only 23% of investors expecting success after an earlier study also came up neutral, according to a poll by ISI Group analyst Mark Schoenebaum.

But some analysts were expecting at least a glimmer of hope, or, in the word’s of JPMorgan’s Christopher Schott on July 16, “not a black and white outcome.” But the outcome couldn’t have been starker.

There is “no path forward” for the intravenuous (or I.V.) version of bapineuzumab in mild-to-moderate Alzheimer’s disease, says Pfizer spokeswoman Victoria Davis. (Earlier-stage studies of a newer version that is injected under the skin are continuing.) “Representatives noted that the secondary endpoints results were not promising, and there were no positive signals from existing subset analyses thus far,” wrote Barclay’s analyst C. Anthony Butler in a note to his clients. “We interpret yesterday’s news as a definitive end to bapineuzumab, and any glimmer of hope is all but extinguished.” Pfizer does note that “These data, and the subgroup and biomarker analyses underway, will further inform our understanding of this complex disease and advance research in this field.”

What’s really surprising about bapineuzumab’s failure is that expectations were as high as they were. And what’s shocking is that Johnson & Johnson spent more than a $1 billion to invest in Elan and get one-quarter of the drug, and that Pfizer (or, rather, Wyeth, which Pfizer bought) and Elan chose to push the drug into broad clinical trials despite a single, uncomfortable fact, which was previously noted by Forbes contributors David Maris and Nate Sadeghi:

Bapineuzumab failed in earlier studies, and Wyeth and Elan decided to plunge forward anyway.

In an earlier, mid-stage study, the drug failed to help patients by a statistically significant margin. The drug didn’t work much at all in patients who carried a genetic mutation in a gene called APOE4, which increases the risk of Alzheimer’s and makes the disease worse. But it seemed to have a profound effect in patients who lacked the APOE4 mutation. The problem is that, in a clinical trial that does not meet its main goal, this kind of subgroup analysis (or, less charitably, data-dredging) is very likely to be due to chance.
T
his is not Monday morning quarterbacking. Plenty of people said this when the results were released in 2008. British Alzheimer’s researcher John Hardy, who came up with much of the basic science behind “bapi,” told Forbes at the time:

“Maybe, maybe, maybe [it works], but I am not convinced. I’m worried they are just looking at noise.”

Wyeth and Elan had plenty of options aside from just plunging ahead. They could have waited for new diagnostic tests to help figure out if the drug was working. They could have done a series of smaller studies to test whether the effects that were being seen were really there. Or, at the very least, they could have conducted late-stage studies only in patients who did not have the harmful APOE4 mutation. (Regulators could have been involved in the decision to test the drug on everybody; that doesn’t make the decision smarter.)

The logic behind going forward probably went something like this: Alzheimer’s is one of the world’s biggest health problems and any drug that can impact it would be simply huge. Even if bapi were not that effective, it could have generated $5 billion in annual sales, easy. It would be crazy not to try, right?

No. The crazy thing was trying. That logic would make perfect sense if it were not for the most difficult fact in drug development: the drug industry’s failure rate and the amount of research and development money spent for each success are both rising at an exponential rate. The number of new medicines invented per billion dollars spent is halved every 9 years.

Bernstein Research analyst Jack Scannell has dubbed this “Eroom’s Law,” not in a Wall Street research note but in Nature Reviews Drug Discovery. He’s also warned his clients that it may not be worth trying to fix drug companies with below-average R&D divisions. Even if you make them as good as the average company, R&D will still lose more money than it makes the way things are going.

Whatever a company’s scientists think the likelihood of a project failing is, it’s probably even worse than they think. With the current state of drug research, bapi wasn’t just a Hail Mary pass, but a Hail Mary pass thrown in gusty gale force wind at a randomly moving target.

What’s worse, these long-shot bets are getting more and more expensive. J&J is taking a $300 million to $400 million charge in the third quarter for discontinuing its share of the trials. Even at a scale of hundreds of millions of dollars, the money could be spent differently. Optimer Pharmaceuticals spent less than $200 million in R&D from the time it went public until the time its first drug, Dificid, was approved.

But bapi isn’t so bad in one regard. Increasingly companies are willing to make bets of billions of dollars almost completely blind, as clinical trials get larger. This goes for Eli Lilly’s Effient and AstraZeneca’s Brilinta, blood thinners that went through huge clinical trials and then failed to garner significant sales. It goes for all the Factor X blood thinners being developed by Pfizer, Bristol-Myers Squibb, J&J, and Bayer whose success will hinge on their bleeding side effects. Darapladib, a pill to fight artery inflammation being developed by GlaxoSmithKline that was one of the reasons for the company’s purchase of Human Genome Sciences, failed its main goals in an artery imaging study. But large studies of the compound went forward anyway.

Doing large studies of new medicines is a good thing – it’s the best way to truly establish both safety and efficacy. But that doesn’t mean, at a time when every drug company is struggling to improve its success rates, that we should be doing as many of these studies as possible. Sure, as former Pfizer research chief John LaMattina writes, drug development is very hard. This is a business where more than one in twenty projects fail. But that’s all the reason not to fly blind.

Even drugs that have built a strong track record in earlier trials fail in the late stages of development. There is no reason to push forward with medicines that have little chance for success.

Industry executives are probably thinking back to the success of drugs such as Plavix and statins like Lipitor and Zocor. But the big trials that proved the worth of those drugs came after the medicines were cleared and marketed, and there was a huge amount of data supporting doing big tests to prove the medicines extended lives. Certainly, sometimes doing a study to prove a drug’s benefit is worth it – but you should be able to prove that the odds of success are high in earlier, smaller, cheaper studies. Industry executives should think back to an earlier precedent: the move in cancer trials pushed by Genentech more than a decade ago to make mid-stage trials mirror approval studies, with control groups and patients who are randomly assigned either to get the drug or not. The result is fewer drugs progressing into large studies without evidence they work.

There is already a good example in Alzheimer’s, with a drug a lot like bapi. Some bapineuzumab skeptics don’t believe that the basic theory behind bapi, that plaques of a chemical are a cause of Alzheimer’s, are true. Amyloid believers think that the drugs just need to be tested earlier in the process. But it’s hard to know the truth, because in Alzheimer’s studies there is no way to even know if all the patients have Alzheimer’s or to measure whether a drug is removing amyloid plaques from their brains.

Genentech, now part of Roche, has come up with one elegant test. It’s testing its own antibody against amyloid, developed by its partner AC Immune, in a study in Colombia in a population of people who are sadly condemned by a rare genetic mutation to develop Alzheimer’s. “If with this trial we show that we’re removing or preventing a beta from accumulating in the brain, and the cognitive decline still happens, I’m going to wonder if maybe the amyloid beta hypothesis is true after all,” said Richard Scheller, executive vice president of research at Genentech. Some analysts think that Pfizer and J&J are keeping an under-the-skin version of bapi in trials like this to show a way to do studies earlier in Alzheimer’s.

Luckily, the strong trend in the industry is to insist, increasingly, on these kinds of proof of concept studies. It is the long-held research strategy at Novartis, and is very much what Elias Zerhouni, the head of research at Sanofi, has in mind when he talks about his plan to improve long-term success rates. If company executives can stick to this discipline, we’ll all benefit. Like good card players, good drug developers need to sit out many more hands than they play.