THIRTY-TWO

BOSTON

Fall 2014–Winter 2015

Dr. Reisa Sperling is a woman about half my size, all smiles and bustling energy. She’s both a neurology professor at Harvard Medical School and director of Alzheimer’s research at Boston’s Brigham and Women’s Hospital. In other words, she’s serious. She’s also full of hope for what she calls her A4 study.

Strictly speaking, the drug that Dr. Sperling is testing has already failed. It’s called solanezumab—let’s call it S-bub for short. The big pharmaceutical company Eli Lilly hoped it would block the forming of amyloid plaques. It didn’t, so it failed its trial. But while S-bub didn’t work on patients who actually had Alzheimer’s, it did seem to help patients at an earlier stage: those who had signs of amyloid buildup but no cognitive impairment as yet.

Maybe the drug wasn’t the problem. Maybe the timing was the issue.

For what she hopes will be the largest Alzheimer’s prevention trial in the country, Dr. Sperling aims to have at least one thousand participants, spread over sixty sites. Each participant will be between sixty-five and seventy-five years old. Each must have two copies of the APOE-e4 gene—one from each parent—but no symptoms yet of Alzheimer’s. Half the group will get S-bub; half will get a placebo. Sperling will track both groups for three and a half years.

Testing a drug for prevention of Alzheimer’s is novel enough. But there’s another twist to the A4 study I find especially intriguing. Sperling wants 20 percent of her one thousand participants to be African Americans. So does the National Institutes of Health, which is providing most of the A4 study’s funding: $36 million. So far, unfortunately, Dr. Sperling has only fifty volunteers overall; of those, only six are African American. Here we are again: same old story. How are we going to learn why African Americans are twice as apt to get Alzheimer’s if none of them will join the A4 study?

Dr. Sperling is doing all she can, visiting black churches, community centers, and more, to get out the word and line up participants. But she’s starting to feel pressure to start on the trial with the fifty or so participants she has. She won’t say where the pressure’s coming from, exactly, but it’s a fact that Lilly is now in a race with another company called Biogen that just won approval to start its own Phase III trial for an almost identical drug.

A five-minute walk from Dr. Sperling’s office is a scientist who may be about to learn exactly how Alzheimer’s works, and in the process give the world a whole new perspective on it, one that may make Alzheimer’s as easy to treat as high cholesterol.

The first thing you notice about Dr. Rudolph Tanzi is his intensity. He grins as he takes your hand; then he’s off and running, rattling off medical jargon with a Boston accent as flat and heavy as any Kennedy’s. At fifty-six, he’s head of Massachusetts General Hospital’s Genetics and Aging Research Unit, and teaches at Harvard Medical School. The hospital has taken over the old Charlestown Navy Yard and spiffed it up, but kept the red brick façade. Dr. Tanzi’s office has a curving, brick-framed window overlooking the Charles River, and a desk dominated by three oversize computer screens, where the answers to Alzheimer’s may lie.

Scientists may argue over who the leading figure in Alzheimer’s research is, but nearly all put Dr. Rudy Tanzi in the top three. In the mid-1980s, he was one of the discoverers of the first Alzheimer’s-related gene, APP (amyloid precursor protein), eventually known by those three variants APOE-e2, e3, and e4. In the mid-1990s, he helped find two more. Now he may be on the verge of his greatest discovery yet.

Dr. Tanzi is excited but cautious: he’s been at this rodeo before. Back in 2001, when he published his book Decoding Darkness, about his early gene searches, he and his team were focused on three new drug trials, all trying to block amyloid plaques. All those trials eventually failed, as one after another of those drugs proved toxic in the human brain.

With that, the whole question of whether amyloid plaques cause Alzheimer’s seemed up for grabs. Maybe it was the tau tangles after all. But in the ongoing debate—amyloid plaques or tau tangles?—Dr. Tanzi remained stubborn. He still felt the plaques were to blame.

On his way to a breakthrough in 2014 that would drastically affect the debate, Dr. Tanzi saw his profile rise in ways he’d never expected. GQ magazine included him in a photo shoot called “Rock Stars of Science,” paired with Aerosmith guitarist Joe Perry. When Dr. Tanzi told the rock legend he’d played organ in bar bands through his twenties, Perry suggested they jam. Dr. Tanzi ended up playing organ tracks on Aerosmith’s next album. (Another GQ rock star of science was our own Dr. Sam Gandy of Mount Sinai.) A chance meeting led to a book collaboration with Deepak Chopra, the mind-and-body expert. Super Brain has since sold one million copies and spun off a PBS series hosted by Dr. Tanzi. But none of this took him away from what he calls his obsessive, almost pathological quest to crack Alzheimer’s.

PET imaging was the key. With it, for the first time, scientists could see how early plaques began to form in people who would eventually get the disease. “We could see that amyloid begins in the brain fifteen to twenty years before symptoms,” Tanzi explained. “By the time you show symptoms, amyloid growth is already plateauing.” Maybe trying to treat the symptoms once they were pronounced was a fool’s errand. “Giving a patient a drug for amyloid is like giving a patient who just had a heart attack some Lipitor,” Dr. Tanzi declared. “You have to give it a lot earlier than that.”

That was the epiphany that led Eli Lilly to retry S-bub on pre-Alzheimer’s patients with amyloid plaques: the A4 study that Dr. Sperling is leading. It’s the epiphany that has since led Biogen to come up with a similar drug. Both use antibodies that may block amyloid.

Last October, as these two drug prospects were squaring off, startling news came from Dr. Tanzi’s lab. Not another new drug to rival those two. Something bigger. A new tool to transform the field and test dozens, hundreds, thousands of possible Alzheimer’s drugs, not over a period of years, but weeks.

“For the first time, and to the astonishment of many of their colleagues,” the New York Times reported of Dr. Tanzi and neuroscience partner Doo Yeon Kim, “researchers created what they call ‘Alzheimer’s in a Dish’—a petri dish with human brain cells that develop the telltale structures of Alzheimer’s disease.” Tanzi and Kim had done it with human embryonic stem cells, growing them as neurons, then giving them Alzheimer’s genes. Over time, the genes acted just as they did in human brains: creating amyloid plaques and tau tangles.

The implications are staggering. Until now, scientists have been forced to test possible new drugs one at a time in mice. Though genetically close to humans, mice are different enough that success with a new drug in mouse models is merely a good indication, not proof, that the drug will work in humans. That’s one reason why Alzheimer’s drug trials have so often failed. Worse, mouse trials take up to eighteen months.

Now that whole paradigm has been turned on its little mouse head. “So instead of waiting a year and a half with a mouse, we can test all twelve hundred approved FDA drugs and about five thousand Phase I safety trial drugs,” Dr. Tanzi told me triumphantly. Drugs, that is, for any and all needs. “You don’t know what might work with Alzheimer’s. Who knows how many unexpected combinations we might get that work against it?”

At the same time, Dr. Tanzi’s “Alzheimer’s in a Dish” trick appears to transform, after thirty years, the great debate over whether Alzheimer’s is caused by amyloid plaques or tau tangles. The answer is…plaques! Or to put it more conservatively: you don’t get Alzheimer’s without plaques. Just as Dr. Tanzi thought all along. “We get plaques in six weeks,” he says of his petri dish stem cells, “then get tangles. If you stop the plaques, you don’t get the tangles.” So tau tangles aren’t the sole cause of Alzheimer’s, as some scientists believed. And they don’t seem capable of causing Alzheimer’s without plaques in the picture somehow.

But while this mechanism may be true in the “petri dish,” when the cells are given the abnormal amyloid gene, the debate isn’t quite settled. Howard Fillit, for one, continues to believe there are many causes of neuronal cell injury in the aging brain, with many of them, such as inflammation, oxidation, energetics failure, neuroprotection, and others being worthwhile drug targets, and beta-amyloid being one among them in the vicious cycle of neuronal injury.

Reisa Sperling has her own doubts, not so much about the science of Dr. Tanzi’s petri dish breakthrough as about how much it matters in regard to getting new drugs to market. Reisa has boundless admiration for what Rudy Tanzi has contributed to the field, but ultimately, she says, it’s about the trials. What works in a petri dish still has to be tested on human beings, and the ways in which new drugs interact with human biology—over a year, or two, or three—can’t be predicted. In most cases, they can’t be controlled, either. So again, what seems like the beginning of the end of the struggle to stop Alzheimer’s is more like the beginning of the beginning. It’s a better place to be than you were before, but you’ve still got a ways to go.

Whether it’s game, set, and match or merely game, Dr. Tanzi has clearly made a profound contribution to Alzheimer’s research. To him, it’s part of the new big picture—and so are those mild-stage antibody drugs that Eli Lilly and Biogen are testing in people who have plaques and tangles, but not yet any symptoms of Alzheimer’s.

“Here’s my dream,” Dr. Tanzi told me, leaning in as if to confide a secret. “Biogen’s antibody opens the door to the notion of a statin for Alzheimer’s.” Statins, of course, are for lowering serum cholesterol levels to clear arteries and reduce the chance of cardiovascular disease. When Dr. Tanzi talks of a statin for Alzheimer’s, he means a drug that works in the same way a statin for heart disease does. “Instead of measuring cholesterol, it’s measuring amyloid,” Dr. Tanzi said with an impish grin. “Instead of a blood test, it’s PET imaging.”

Dr. Tanzi sees a time, not far in the future, when a doctor looks at the PET amyloid image of a forty-year-old’s brain and says, “You have way too much amyloid for a forty-year-old; you need to take a moderator like Biogen’s.”

Maybe it’s a little white pill like Lipitor, Dr. Tanzi added, that can bring your amyloid down like Lipitor brings down cholesterol. So a doctor treats you before you have cognitive issues. “Remember these words,” Dr. Tanzi told me: gamma secretase modulator.

That’s the enzyme that will keep those amyloid plaques from forming, Tanzi explains, without doing any damage in the process—and keep a forty-year-old from getting the disease in twenty or thirty years.

—

Last night, B. and I curled up at home to watch the Oscars. Most of it was so boring that you could have Alzheimer’s and not miss a thing. But toward the end of the broadcast, we perked up as the nominees for Best Actress were named. One was Julianne Moore, for her heartbreaking performance in Still Alice as a fifty-year-old dealing with early-onset Alzheimer’s. I had taken B. to see the movie, and she’d loved it, even as it provoked a lot of tears. The envelope was opened, the card pulled out—and wow! Julianne Moore won! More surprising was what happened next. B. whooped with delight, pumped her fist, and cried, “You go, girl!”

Even now, we have moments like that.

Both of us, I think, have accepted that B.’s illness will only get worse. Those new drugs from Eli Lilly and Biogen, those breakthroughs in Boston, the new focus on prevention—we’re simply too late for that, and we know it. I do have every confidence that in my lifetime, Alzheimer’s will no longer be the all-powerful enemy that it is today. It will be, as the doctors put it, a managed disease, probably a treatable disease, maybe even a reversible disease. You just can’t have 15 million Americans walking around in a fog, wandering off into the night. The drug companies will come up with a host of new drugs for the reasons they always do: public need and corporate profit. There will be answers. And fortunes will be made.

I’m hopeful—confident—that all this will come to pass. It’s just hard right now to feel too happy. As I write these words, I’m at the dining table, looking out over the bay, and B. is on the living room sofa, fiddling with a word game she no longer knows how to play. Barring a miracle, those medical breakthroughs won’t come in time to save a woman who has moderate-to-severe Alzheimer’s, a woman who for twenty-two years has been my beloved wife.

I feel her over there, sitting quietly, waiting again for me to tell her what to do. I think what we’ll do is get Bishop, and head down to the beach for a long winter walk, before the last of the daylight is gone.

LESSONS LEARNED

THE BRAIN REGISTRY

The easiest way to make a difference with Alzheimer’s is to sign up to participate in a brain study trial. It helps to be sixty or over, but you certainly don’t need to have Alzheimer’s—or even worry that you might!—to participate. Brain-healthy participants are just as important as those who aren’t: healthy “control” groups are an essential part of most trials, especially research trials, in which participants are simply observed over time.

Living in a major metropolitan area helps—that’s where the medical centers are, and where research and drug trials for Alzheimer’s are apt to be found. But there’s another way to join, no matter where you live, and now I’m talking black or white, with or without Alzheimer’s. It’s called the Brain Registry.

Back at that Alzheimer’s benefit luncheon, I met Dr. Michael Weiner, an internist and medical scientist who’d often worked over the years with our doctor, Howard Fillit. Dr. Weiner saw that with Alzheimer’s research, the lack of trial participants was a stumbling block. “It’s the biggest problem,” he explained to me. “The high cost and difficulty of getting people into studies. Recruiting people, identifying them, screening them—it’s a very messy, slow process. Most researchers still interview ten people for each one they get.”

The other problem, Dr. Weiner saw, was that every study recruited for itself. “If two investigators in San Francisco are both doing neuroscience research, they will each have their own research teams and clinical trials and recruit participants individually. It’s crazy!”

This year, Dr. Weiner created the Brain Registry, a website to enlist trial participants across the country. The trials are for various diseases, but Alzheimer’s is one of them. All it takes is being eighteen or older and committing three hours a year to cognitive testing. As scientists come up with new drugs to test on Alzheimer’s, they’ll need participants—and now they may find them through the Brain Registry, instead of putting ads in college newspapers or on Craigslist.

After just six months in operation, the Brain Registry has signed up ten thousand candidates already. To date, most of those are in the San Francisco Bay Area, because that’s where Dr. Weiner lives and works. But this is just the start. “Our goal is to go global,” he told me. “And all the data that comes from those trials will be shared with anyone who might benefit from it. Clinical data, that is: a participant’s personal data is fiercely guarded.”

Go for it! Visit www.brainhealthregistry.org.

A NASTY LITTLE SECRET

Some months ago, I found myself scanning the obituaries with an interest I’d never had before. Oh, sure, I read the obits of people I’d heard of or known. But I didn’t go down the day’s list of paid obits in the New York Times, looking for how each person had died. Now I did—and what I found, to my surprise, is that almost no one died of Alzheimer’s. I guess in a way I was looking for comfort in numbers—or maybe it was misery in search of company. I didn’t find it. And why was that, with Alzheimer’s the sixth-highest cause of death in the country—or even the third, depending on which organization is doing the counting?

The fact, as Dr. Fillit explained, is that many of those people had died of Alzheimer’s; it just wasn’t listed as the cause of death. Strictly speaking, it was the indirect cause. And a lot of grieving families preferred to list, as the cause of death, the final complication that Alzheimer’s led to: a stroke, heart attack, or pneumonia.

Pneumonia is the most common of those end-stage courses. By then, a patient is immobile, which affects his lungs’ capacity to expand and manage secretions properly. That leaves him susceptible to infections, including pneumonia. An inability to swallow may allow foods, liquids, and saliva to enter his airways, increasing the odds of pneumonia. In fact, as many as two-thirds of the people who die from Alzheimer’s are listed, in their obits, as dying from pneumonia. Or complications from pneumonia. Or just “a long illness.”

The hospitals are partly—maybe mostly—to blame. They’re being too literal in listing pneumonia as the cause of death. Technically they may be right, but with Alzheimer’s, pneumonia is merely the grace note. Or as that grim saying has it, the old man’s friend, since it’s relatively painless and the patient dies in bed.

The hospital may list pneumonia to be medically exact, but the family knows better. Any family whose loved one has just died of Alzheimer’s can request that Alzheimer’s be listed in an obituary as the cause of death, but all too few do. Some families may just be too grief-stricken to think about this, but let’s be blunt: a lot of families stick with the hospital’s listed cause of death to avoid the still-strong stigma of Alzheimer’s, both on behalf of their just-deceased loved one—and themselves.

I say the hell with that.

You want to see Alzheimer’s get more federal funding? You want to keep a next generation from suffering as much with this awful disease as your family has? Then do the right thing: insist that Alzheimer’s be listed as the cause of death. Change comes with numbers. Political change, I mean. Dr. Fillit is sure that far more Americans have Alzheimer’s right now than the 5.2 million estimated by the Alzheimer’s Association. He thinks the real number is 10 million, maybe more. Where are those other five million? Hiding in their houses—or being hidden—their illness dismissed as routine aging, their deaths recorded as anything but Alzheimer’s. The bigger the real number of Alzheimer’s patients, the bigger the real number of Alzheimer’s deaths, the more our government will be pushed into giving it the funding it deserves—as the third-biggest killer in our country.

When it comes, don’t be embarrassed to list the true cause of death for your loved ones. That, along with signing up with the Brain Registry, may be the most significant move you can make to help manage, and ultimately stop, this disease.

THE SPIRITUAL SIDE

For better or worse—well, let’s just call it worse—spirituality has played no real part in B.’s adult life or mine. B. remembers those door-to-door days selling The Watchtower as if they were last week, but neither her father’s faith as a Jehovah’s Witness nor her mother’s as a Baptist left much imprint on her. As for me, I’ve just never felt the need to enter a church. Even in us, though, Alzheimer’s has stirred something that feels close to spiritual.

It starts with questions. Why do any of us have to suffer this terrible disease, knowing that our minds and memories are being dulled and destroyed one by one? What God could possibly let our brains and bodies disintegrate in this way? If there is a God, and if he does allow this kind of suffering, what message might he be trying to send? Is the point, perhaps, for all of us to appreciate, more keenly, what life we have left? Is it about living in the moment—truly in the moment, the way only a person with Alzheimer’s can?

Lately, I’ve been doing some reading on this. You wouldn’t believe how many technical papers there are out there on spirituality and Alzheimer’s. As if scientists could measure spirituality like blood pressure! One theme that comes up a lot is how helpful religious faith is for people with mild-stage Alzheimer’s. Not only does it ease their anxiety: it seems to slow their cognitive decline. For a boy from Bed-Stuy who never saw much point in church, that’s a very persuasive reason to start going. The Alzheimer’s Foundation of America’s website notes three academic papers that all reached the same conclusion: regular attendance at church kept participants’ minds sharper. Maybe it was praying, especially prayers known from childhood—and hymn singing, too. That kind of weekly joining in on long-familiar words and music might stimulate the temporal lobes, the scientists suggested, or increase memory-strengthening chemicals in the brain. Being involved with a church and its congregations, the scientists added, might ease anxiety. It might also provide comfort and hope. The scientists stopped short of proselytizing, but did point out that hundreds of studies had shown that religious individuals cope better with stress and depression.

Googling around, I found one academic paper with just the title I wanted: “Using Spirituality to Cope with Early-Stage Alzheimer’s Disease.” Of course B. was now a bit past the early stage, but I still identify the two of us as dealing with early-stage Alzheimer’s: a little lingering denial, I guess. In any case, this paper, from a team at Vanderbilt University, suggested that spirituality in any manifestation has a beneficial effect. Some of the trial participants defined their spiritual world as nature, others as a pragmatic, guiding principle in their lives, still others as the explanation for suffering and setbacks. Some, to be sure, also associated spirituality with God and churchgoing. But I was gratified to think that a belief in God wasn’t the only ticket you could punch to get the physical and psychological benefits of spirituality.

Sometimes now, B. and I talk about life and what it means, what’s important and what we can do to get the most from what remains. I’d like to think that in the next years, we’ll do more talking like this.

One comforting thought is that even as B. continues to change, she’s still the same person I married, twenty-two short years ago. Which is to say that even as Alzheimer’s diminishes her mind, and periods of anger and depression increase, the essence of who she is—her soul—remains the same.

For now, remarkably, B. still looks as beautiful as she ever was. Not only that: she’s fit enough to walk the length of Manhattan in red spike heels! The moments of dislocation and dysfunction are increasing, the inability to follow what’s said, or to do tasks that take multiple steps—all this points in the obvious, inevitable way. For now, though, she’s still more B. than not.

When those changes do occur, I hope that I’ll be able to do what I’m hoping you can do, too: not lose sight of the soul within. Keep communicating with the soul you know and love, even if she grows immobile and seems not to react. Studies have shown that patients with end-stage Alzheimer’s do hear, think, and feel, even if they seem to have vanished from the ruined bodies they inhabit. I know I’ll be right there, holding the hand of the woman I love. I guess that’s spirituality, too, of the human spiritual kind.

Good luck to us all.