NEW YORK CITY
Fall 2014
In the sixteen years that ADDF has been in operation, Dr. Howard Fillit has steered over $70 million from the Lauders and others to fund more than 450 programs in eighteen countries, including more than 65 biotechs. Some are start-ups that would have gone unfunded without the ADDF, since venture capitalists in the medical field are wary of small biotechs in general, and Alzheimer’s in particular.
The biggest triumph so far for ADDF has been funding the original research that led to PET imaging for the brain—the same technology that showed those plaques in B.’s brain and confirmed her diagnosis. The story of neurological PET imaging also shows how the ADDF works—and how it may yet find the ultimate Alzheimer’s drug. In 2004, it began funding a start-up program at the University of Pennsylvania that had the idea of injecting a radioactive molecule that could bind to the beta-amyloid in the brain and track it as it went through the brain. The places where the radioactive material bound to the amyloid indicated amyloid plaques. In 2005, the idea was spun out as a biotech called Avid Radiopharmaceuticals, with some $7–8 million from investors to ramp it up. Five years later, the giant drug company Eli Lilly bought Avid for almost $800 million. In 2012, the PET amyloid imaging test from Avid became the first diagnostic test for Alzheimer’s to market with FDA approval.
Imagine! One could detect the presence of beta-amyloid in the brain without having to do a brain biopsy or an autopsy! This would surely improve the diagnosis of Alzheimer’s disease, showing with certainty who had it—and who didn’t. That was big, but as Howard is the first to admit, PET brain imaging doesn’t treat the disease, let alone cure it. Medicare, as a result, refuses to pay for the test—because the test doesn’t change the outcome. Everyone still dies.
Howard is furious about that. Before PET imaging, as he points out, diagnosing Alzheimer’s was a guessing game based on symptoms. Here was a test that clearly distinguished who had Alzheimer’s from who didn’t. And for people with memory problems, the reassurance that they don’t have Alzheimer’s, but might have a treatable cause, could be priceless. Wasn’t that worth perhaps three thousand dollars of reimbursement per patient? Certainly, there are many other tests for other diseases that cost as much or more. But not according to Medicare. So today, only those who can afford the test get it.
Despite that impediment, PET amyloid brain imaging has been a breakthrough in how brain researchers do clinical trials. Today, practically all patients who enter into a clinical trial for Alzheimer’s receive the test. It turns out that about 30 percent of people entering these trials prior didn’t even have the disease. This really confounded the studies, making them very difficult to interpret, and could account for some of the drug failures. PET imaging has eliminated that problem.
The test has also led to game-changing prevention studies. Now, as Howard told me, we can see Alzheimer’s developing up to twenty years before someone begins to exhibit the first symptoms. This is truly revolutionary and suggests a future in which early detection leads to early-stage drugs that make a real difference at last.
I took all this in, but finally I held up my hand. Okay, I said, I got it. Alzheimer’s was a challenge, genomics hadn’t given us the magic bullet, and PET imaging, as helpful as it is, doesn’t cure or stop the disease. But surely there were drugs in the pipeline—somewhere—that an insider like Howard knew about, right? For an awful disease that afflicts 5.2 million Americans? Above all I wanted news of drugs on the way for early-onset Alzheimer’s, the kind that B. has. I knew that genes played a key role in early-onset; why not new, gene-targeted drugs? I didn’t know much more than that, because I’d shrugged off the scientific jargon; I’d assumed it was all over my head. Now I wanted to know it all, and found I could take in a lot more than I’d thought. When your loved one is fighting a deadly disease, it’s amazing how much you can retain, after all, of the genetics, the neurobiology—all that stuff. Because maybe if you learn it, and concentrate on it more intensely than your busy doctor, who has so many other patients to tend, you might hit on something that could, perhaps, be useful. Some treatment not yet tried, some alternative medicine not yet in common use. I mean, why not, right?
Howard explained that we do know more about the role one particular gene plays in early-onset Alzheimer’s. It’s called APOE, and all of us inherit a form of it from each of our parents. The question, with each parent, is which form we inherit. APOE-e2 and APOE-e3 are good guys: they move cholesterol and other fats through the bloodstream and out through the liver. In fact, people with APOE-e2 are protected from Alzheimer’s disease. Without APOE-e2 and APOE-e3, those fats would just accumulate, restricting blood flow and leading to heart disease, ultimately to heart failure. But then there’s APOE-e4, which is definitely a bad actor. Because it contains a genetic flaw, it gums up the job that APOE-e2 and APOE-e3 do, and clearly has something to do with Alzheimer’s. If one of your parents passed on the APOE-e4 variant to you, your chances of getting early-onset Alzheimer’s go up. If you have double APOE-e4—one from each parent—your risk of getting Alzheimer’s is 15 to 20 times that of the normal population. Also, you’ll get the disease a decade sooner, so sixty-five rather than seventy-five years old, on average. That doesn’t mean everyone with APOE-e4 will get Alzheimer’s—many will not, which unfortunately only increases the mystery of how APOE-e4 works.
Scientists have known about APOE-e4 for over twenty years—but that doesn’t mean they have a drug for it yet. They don’t. “The genomics is scientifically interesting,” Howard said, “but translating a gene into a drug is incredibly hard.”
Also, the fact that APOE-e4 is involved doesn’t mean that APOE-e4 is the cause of Alzheimer’s. It may just be a risk factor. All scientists know for sure is that it’s associated with Alzheimer’s and seems to increase the risk that more plaques will form and the cascading effects of Alzheimer’s will follow.
How to block APOE-e4 is the question. Two of Howard’s funded research teams are developing a gene therapy using APOE-e2 to counteract APOE-e4. The idea is to isolate the DNA that codes for APOE-e2 (the “good” APOE), put it into a very safe virus—like putting a passenger into a little space pod—and then inject it into the brain of a person with APOE-e4. The APOE-e2 may offset the bad effects of APOE-e4. That may lessen the odds that amyloid plaques will form and that a person will get early-onset Alzheimer’s. But does that mean a drug is on its way for early-onset patients like B. who’ve already gotten the disease and are passing into its middle stages? No, Howard told me, it doesn’t.
With late-onset Alzheimer’s, coming up with new drugs may be even more of a challenge because it involves aging. APOE-e4 is associated with it. But so are various other aging-related processes and symptoms. We know the cast of characters, most of them anyway. But we don’t know nearly enough about how the play unfolds. “The only thing we know is that aging is the leading risk factor,” Howard told me.
That isn’t to say that aging causes Alzheimer’s. There isn’t necessarily any direct cause-and-effect link between the two, or else everyone would get Alzheimer’s as they age. But something in the biology of aging is clearly involved.
“When you’ve been on earth for seventy-five or eighty years, getting repeatedly hit by toxins, inflammations, and free radicals, not to mention actually hitting your head—think of soccer players or football players or boxers—you’ve probably sustained neuronal injury,” Howard explained. “One of the ways the body may respond is by producing amyloid. And it appears the clearance mechanisms for amyloid in the brain work better for young people, less well in older people. But there are many other mechanisms to cause neuronal injury as well.”
We can’t help having been knocked on the head now and again. Nor can we help having lived sixty or seventy years with all the neurological wear and tear involved. So many of us may accumulate our share of amyloid plaques by the time we reach old age. But just having amyloid plaques doesn’t mean you get late-onset Alzheimer’s, either. Some octogenarians have lots of plaques and never forget a phone number, much less get the disease. Amyloid does seem to play a supporting role. Maybe even a lead role. But not, perhaps, the only role. So what else is involved? Mostly, what those other triggers have to do with is, in the broadest sense, lifestyle.
Just in the past few years, Howard explained, the science has become much clearer on the subject of health and its consequences, for better and worse, on what they call the noncommunicable diseases: heart disease, diabetes, hypertension, and, yes, Alzheimer’s. Fitness and a good diet keep them at bay; lack of exercise and a couch-potato diet help bring them on. The unmistakable sign of the latter is obesity, so rampant in America in every age and socioeconomic category. Obesity, and the bad habits associated with it, has been shown to be a risk factor for Alzheimer’s.
Diet and exercise aren’t just beneficial in some vague, feel-good way, Howard explained. They literally turn on genes that help us. A whole new science called epigenomics regards genes as a sort of circuit board, to some extent under our control. Simply by changing our diet, we can cause a whole circuit board of genes to be either active (or “expressed”) or inactive (“not expressed”). How cool is that? More and more, the interaction between genes and the environment we expose them to is being seen as hugely significant. Unfortunately, these diet and exercise genes are probably most effective in fighting Alzheimer’s early on—ideally, years before the disease can be diagnosed, when mere wisps of Alzheimer’s-like symptoms go unnoticed.
Exercise and diet, Howard told me, actually stop the brain from shrinking. “With cognitive aging, our brains shrink by about point-four percent a year,” he said. “Recent studies have shown that with brisk daily walks over a period of months, certain parts of people’s brains actually get bigger.
“The brain is like a muscle,” Howard added. “The more you build it, the more you will protect it from all the toxicities that affect it.”
Okay, I said. Exercise, diet—I got it.
And no drinking, Howard added. That went for caregivers, too, not just patients.
The recent findings about Alzheimer’s and lifestyle haven’t led to new drugs yet, Howard said. But there is some good news in all this. Drugs that work for the other noncommunicable, lifestyle-linked diseases—hypertension, diabetes, heart disease—might work for Alzheimer’s, too. Repurposing—that’s what they’re doing with these established drugs now.
The great advantage of repurposed drugs is that they’re approved and on the market for at least one condition already. So that $1–2 billion in development? It’s already been spent. And proving that a drug designed for some other disease also happens to work against Alzheimer’s is a whole lot easier and cheaper than starting from scratch. Repurposing drugs isn’t like getting secondhand stuff. Some repurposed drugs have gone on to make far more money by their new use than their original one. Exhibit A: Viagra, originally designed for pulmonary hypertension.
So far, unfortunately, Viagra appears to have no effect on Alzheimer’s. But other hypertension drugs may. One class focuses on angiotensin receptors in the blood that under the wrong circumstances can narrow blood vessels, increase blood pressure, and force the heart to work harder. Angiotensin receptor blockers (ARBs) can help relax the blood and reverse that process. It turns out that in the part of the brain called the hippocampus, where Alzheimer’s begins, there are also angiotensin receptors that are neuro-protective. The ARBs may be able to improve brain blood flow and decrease the deposits of amyloid that grow into amyloid plaques in animals. A recent study at Johns Hopkins University showed that certain blood pressure medicines—in the same bailiwick as hypertension drugs—led to a dramatically lowered risk of Alzheimer’s, as much as by 50 percent. But as with so many of these promising results, this one needs a lot more research.
A diabetes drug called liraglutide looks promising, too. It helps diabetics take up insulin. Turns out, it does good things for the brain, too. Specifically, it seems to prevent the buildup of amyloid plaques in animals, to repair neurons, and to keep synapses working. The brain, as a result, works better and can better cope with stress and toxic influences. One study with mice suffering from late-stage Alzheimer’s found that liraglutide managed to reduce amyloid plaques in the brain by 30 percent after two months. A first clinical trial of liraglutide, funded by the ADDF among others, is under way.
For heart disease, of course, statins such as Lipitor are used to lower the cholesterol that blocks arteries and leads to trouble. In recent years, statins have seemed to hold the promise of protecting against Alzheimer’s, too—so much so that they’ve gone through three clinical trials for it. Unfortunately, they failed to meet their clinical test goals. But Howard is still cautiously optimistic about statins. “We don’t know if statins failed because they don’t really play a role—or because we treated people too late,” Howard explains. But at least one new study—not a clinical trial—suggests that in high doses, statins help prevent dementia. So here again, the jury is out.
Another repurposing possibility is drugs for rheumatoid arthritis. Enbrel is a so-called biologic drug that has proved effective in blocking the inflammation of psoriasis as well as rheumatoid arthritis; it seems promising as an agent to fight inflammation in the brain, too. That could make it a critical tool against Alzheimer’s, since inflammation is an important part of neuronal injury. In a recent test, Enbrel slowed cognitive decline in only a small subset of Alzheimer’s patients, so more clinical studies need to be done.
The Mediterranean diet, by the way, is also an anti-inflammatory and antioxidant diet. There’s no doubt that inflammation, designed to help us heal, can also do us harm. That happens when our immune systems, for complex and not wholly understood reasons, start attacking us instead of defending us. That prompts the reaction of inflammation—sometimes directed at our nervous system, sometimes at our skin, and in the case of Alzheimer’s, our brains. The foods we eat can cause, or prevent, oxidation and inflammation. In addition to the staples of a Mediterranean diet—the fruits and vegetables, the fish, the olive oil, and so forth—certain spices, and garlic, can also fight inflammation. Dr. Christopher Cannon of Harvard Medical School treads a careful line here. “Although specific studies haven’t yet been done on some of the popular anti-inflammatory eating plans, the related Mediterranean diet has been studied and is associated with improved outcomes in some diseases.”
The Mediterranean diet isn’t the only prospect that nature gives us. All of us have a protein in our brains called brain-derived neurotrophic factor, or BDNF, and nerve growth factor (NGF), which do really good things for us—and may do even more than we know. Both BDNF and NGF affect the function of the hippocampus, that part of the brain so integral to memory. When we’re young, they help brain cells grow and communicate with one another, literally increasing the brain’s size and capabilities. Throughout our lives, they keep doing that; the process is what’s called neuroplasticity. At the same time, BDNF and NGF may protect our brain cells from injury related to inflammation or oxidation, or even from the toxic effects of beta-amyloid.
The only problem with BDNF and NGF is that they’re hard to use as drugs. They degrade in the stomach if taken orally, and would be hard to administer by injection. Howard’s foundation has funded scientists at Stanford and elsewhere to develop drugs that mimic the effects of BDNF and NGF and protect against all the various kinds of brain injury that natural BDNF and NGF address. The drug developed at Stanford that mimics NGF is now in clinical trials. Meanwhile, we can all try to boost our BDNF, not only with the right diet and exercise, but with omega-3 oils. Though the science on omega-3s indeed remains uncertain, there’s no harm in them and—anecdotally at least—much potential benefit. Yet another possible BDNF booster is sunlight. A team at Leiden University in the Netherlands has found that blood levels of BDNF increased among their participants in the sunniest months, and decreased during those short Scandinavian winter days. Maybe heading south for the winter makes even more sense than we knew.
Vaccines are another promising approach. Monoclonal antibodies, a kind of vaccine against beta-amyloid and even against tau, are in development by a number of pharmaceutical companies. So far, the drugs have not been very promising, though in a recent small clinical trial, an anti-beta-amyloid vaccine from Biogen raised hopes. Eli Lilly has an anti-amyloid antibody, too. Neither so far does the trick completely, the way we expect vaccines to do. Still, both vaccines slow cognitive decline in early-stage patients. So vaccines do have potential; but it’s likely we will need a cocktail of drugs, as in AIDS, to come to grips with the disease.
If he had to guess, I asked Howard, where would he say the first significant Alzheimer’s drug will come from? Which approach? And by when?
Howard shook his head.
“We don’t know where the first effective drugs are going to come from.” On his desk, he keeps a little plaque his daughter gave him. “It’s a quote from Einstein,” he said with a wry smile. “ ‘If we knew what we were doing, we wouldn’t call it research.’ ”
Damn that disease. I’m no scientist; no politician, either. I can’t invent a new drug, nor a cure. But I can see how desperately one is needed, and maybe in my own way I can help raise awareness—help put pressure on our public and private sectors to steer more money to research and get the job done.
By now I’ve realized that the chances of a silver-bullet drug coming along in time to save B. are slim at best. I’ve had to confront that reality after all these months of seeing her get steadily worse. Her all-night wander broke my heart—made her even more precious. It’s also forced me to accept that we aren’t at “mild stage” now. Just keeping B. happy in the time she has left—that’s what I’m aiming for now. But for all the others who come after her—beautiful people with dwindling minds—I can push, and pressure, and politicize, until we get the breakthrough after all.