The Secret of Aging — and How to Slow It Down

Emily Gurnon wrote . . . . . .

What makes some people age more quickly than others? What exactly is aging? And can we do anything about the speed at which we grow old? Authors Elizabeth Blackburn, a molecular biologist, and Elissa Epel, a health psychologist, offer answers in a fascinating book, “The Telomere Effect: A Revolutionary Approach to Living Younger, Healthier, Longer.”

In 2009, Blackburn was one of three scientists awarded the Nobel Prize for their research on telomeres (protective DNA at the ends of chromosomes) and how they protect chromosomes. Epel, one of the 2016 Next Avenue Influencers in Aging, studies how chronic stress accelerates aging, with a focus on telomeres. Both authors work at the University of California, San Francisco.

The following is excerpted from “The Telomere Effect” by Elizabeth Blackburn, Ph.D. and Elissa Epel, Ph.D. Copyright (c) 2017 by Elizabeth Blackburn and Elissa Epel.

It is a chilly Saturday morning in San Francisco. Two women sit at an outdoor cafe, sipping hot coffee. For these two friends, this is their time away from home, family, work, and to-do lists that never seem to get any shorter.

Kara is talking about how tired she is. How tired she always is. It doesn’t help that she catches every cold that goes around the office, nor that those colds inevitably turn into miserable sinus infections. Or that her ex-husband keeps “forgetting” when it’s his turn to pick up the children. Or that her bad-tempered boss at the investment firm scolds her — right in front of her staff. And sometimes, as she lies down in bed at night, Kara’s heart gallops out of control. The sensation lasts for just a few seconds, but Kara stays awake long after it passes, worrying. Maybe it’s just the stress, she tells herself. I’m too young to have a heart problem. Aren’t I?

“It’s not fair,” she sighs to Lisa. “We’re the same age, but I look older.”

Two faces of age

She’s right. In the morning light, Kara looks haggard. When she reaches for her coffee cup, she moves gingerly, as if her neck and shoulders hurt.

But Lisa looks vibrant. Her eyes and skin are bright; this is a woman with more than enough energy for the day’s activities. She feels good, too. Actually, Lisa doesn’t think very much about her age, except to be thankful that she’s wiser about life than she used to be.

Looking at Kara and Lisa side by side, you would think that Lisa really is younger than her friend. If you could peer under their skin, you’d see that in some ways, this gap is even wider than it seems. Chronologically, the two women are the same age. Biologically, Kara is decades older.

Does Lisa have a secret — expensive facial creams? Laser treatments at the dermatologist’s office? Good genes? A life that has been free of the difficulties her friend seems to face year after year?

Not even close. Lisa has more than enough stresses of her own. She lost her husband two years ago in a car accident; now, like Kara, she is a single mother. Money is tight, and the tech startup company she works for always seems to be one quarterly report away from running out of capital.

What’s going on? Why are these two women aging in such different ways?

The answer is simple, and it has to do with the activity inside each woman’s cells. Kara’s cells are prematurely aging. She looks older than she is, and she is on a headlong path toward age-related diseases and disorders. Lisa’s cells are renewing themselves. She is living younger.

Why do people age differently?

Why do people age at different rates? Why are some people whip smart and energetic into old age, while other people seem much younger and are sick, exhausted, and foggy? You can think of the difference visually:

Our healthspan is the number of years of our healthy life. Our diseasespan is the years we live with noticeable disease that interferes with our quality of living. Lisa and Kara may both live to 100, but each has a dramatically different quality of life in the second half of her life.

Healthspan vs. diseasespan

Look at the first white bar above. It shows Kara’s healthspan, the time of her life when she’s healthy and free of disease. But in her early 50s, the white goes gray, and at 70, black. She enters a different phase: the diseasespan.

What is the diseasespan?

These are years marked by the diseases of aging: cardiovascular disease, arthritis, a weakened immune system, diabetes, cancer, lung disease and more. Skin and hair become older looking, too. Worse, it’s not as if you get just one disease of aging and then stop there. In a phenomenon with the gloomy name multi-morbidity, these diseases tend to come in clusters. So Kara doesn’t just have a rundown immune system; she also has joint pain and early signs of heart disease. For some people, the diseases of aging hasten the end of life. For others, life goes on, but it’s a life with less spark, less zip. The years are increasingly marred by sickness, fatigue and discomfort.

At 50, Kara should be brimming with good health. But the graph shows that at this young age, she is creeping into the diseasespan. Kara might put it more bluntly: she is getting old.

Lengthening the healthspan

Lisa is another story.

At age 50, Lisa is still enjoying excellent health. She gets older as the years pass, but she luxuriates in the healthspan for a nice, long time. It isn’t until she’s well into her 80s — roughly the age that gerontologists call “old old” — that it gets significantly harder for her to keep up with life as she’s always known it. Lisa has a diseasespan, but it’s compressed into just a few years toward the end of a long, productive life. Lisa and Kara aren’t real people — we’ve made them up to demonstrate a point — but their stories highlight questions that are genuine.

How can one person bask in the sunshine of good health, while the other suffers in the shadow of the diseasespan? Can you choose which experience happens to you?

The terms healthspan and diseasespan are new, but the basic question is not. Why do people age differently? People have been asking this question for millennia, probably since we were first able to count the years and compare ourselves to our neighbors.

At one extreme, some people feel that the aging process is determined by nature. It’s out of our hands.

Today there are plenty of people who feel that nurture is more important than nature — that it’s not what you’re born with, it’s your health habits that really count.

The significance of telomeres on aging

We’re going to show you a completely different way of thinking about your health. We are going to take your health down to the cellular level, to show you what premature cellular aging looks like and what kind of havoc it wreaks on your body — and we’ll also show you not only how to avoid it but also how to reverse it. We’ll dive deep into the genetic heart of the cell, into the chromosomes. This is where you’ll find telomeres.

Telomeres, which shorten with each cell division, help determine how fast your cells age and when they die, depending on how quickly they wear down. The extraordinary discovery from our research labs and other labs around the world is that the ends of our chromosomes can actually lengthen — and as a result, aging is a dynamic process that can be accelerated or slowed, and in some aspects even reversed. Aging need not be, as thought for so long, a one-way slippery slope toward infirmity and decay. We all will get older, but how we age is very much dependent on our cellular health.

We are a molecular biologist (Liz) and a health psychologist (Elissa). Liz has devoted her entire professional life to investigating telomeres, and her fundamental research has given birth to an entirely new field of scientific understanding. Elissa’s lifelong work has been on psychological stress. She has studied its harmful effects on behavior, physiology and health, and she has also studied how to reverse these effects. We joined forces in research 15 years ago, and the studies that we performed together have set in motion a whole new way of examining the relationship between the human mind and body.

To an extent that has surprised us and the rest of the scientific community, telomeres do not simply carry out the commands issued by your genetic code. Your telomeres, it turns out, are listening to you. They absorb the instructions you give them. The way you live can, in effect, tell your telomeres to speed up the process of cellular aging.

But it can also do the opposite. The foods you eat, your response to emotional challenges, the amount of exercise you get, whether you were exposed to childhood stress and even the level of trust and safety in your neighborhood — all of these factors and more appear to influence your telomeres and can prevent premature aging at the cellular level. In short, one of the keys to a long healthspan is simply doing your part to foster healthy cell renewal.

For healthier aging

Your cellular health is reflected in the well-being of your mind, body, and community. Here are the elements of telomere maintenance that we believe to be the most crucial for a healthier world:

  • Evaluate sources of persistent, intense stress. What can you change?
  • Transform a threat to a challenge appraisal.
  • Become more self-compassionate and compassionate to others.
  • Take up a restorative activity.
  • Practice thought awareness and mindful attention. Awareness opens doors to well-being.
  • Be active.
  • Develop a sleep ritual for more restorative and longer sleep.
  • Eat mindfully to reduce overeating and ride out cravings.
  • Choose telomere-healthy foods like whole foods and omega-3s; skip the bacon.
  • Make room for connection; disconnect from screens for part of the day.
  • Cultivate a few good, close relationships.
  • Provide children quality attention and the right amount of “good stress.”
  • Cultivate your neighborhood social capital. Help strangers.
  • Seek green. Spend time in nature.

Source: Market Watch

For Seniors, Treatment for One Eye Disease May Cause Another

Dennis Thompson wrote . . . . . .

Drugs that preserve vision in people with the eye disease called age-related macular degeneration might increase the risk of another eye condition — glaucoma, a new study suggests.

People who received at least seven eye injections of the drug bevacizumab (Avastin) each year to treat macular degeneration have a higher risk of eventually needing surgery to treat glaucoma, the Canadian study found.

But, the researchers aren’t suggesting that people forgo these treatments for macular degeneration. These drugs help stave off a previously untreatable cause of blindness in the elderly, and should continue to be used, the researchers said. And, if glaucoma does develop, treatments are available.

“Even though there may be a risk here, this doesn’t mean you should not be getting injections for macular degeneration,” said study lead author Dr. Brennan Eadie. He’s an ophthalmology resident at the University of British Columbia in Vancouver.

“This is something we should monitor for, with the understanding there is a real risk of needing glaucoma surgery if the pressure remains elevated,” Eadie said.

The study was published in the journal JAMA Ophthalmology.

Bevacizumab helps treat macular degeneration by blocking a substance that promotes the development of new blood vessels called vascular endothelial growth factor (VEGF).

Bevacizumab and other anti-VEGF drugs have revolutionized the treatment of “wet” macular degeneration, said Dr. Michael Kass. He’s a professor of ophthalmology at the Washington University School of Medicine in St. Louis.

About one in five people with macular degeneration suffers from the wet form of the disease. In wet macular degeneration, new and abnormal blood vessels grow in the eye and cause rapid loss of vision, according to the American Academy of Ophthalmology.

“Sometimes you can grow blood vessels where you don’t want them,” said Kass, who wrote an accompanying editorial for the new study. “In the example of macular degeneration, you don’t want extra blood vessels growing underneath the retina and then leaking fluid or blood.”

While the anti-VEGF drugs have revolutionized the treatment of macular degeneration, isolated cases of increased fluid pressure in the eyes of patients receiving these injections have been reported, Eadie and Kass said.

“The retina doctors here in Vancouver were noticing that patients’ pressures were elevated with time, over several months of giving these injections to certain people,” Eadie said.

Glaucoma occurs when fluid pressure increases so much inside the eyeball that it damages the optic nerve. Eye drops or laser surgery can be used to reduce this pressure, but in extreme cases doctors may have to perform surgery that allows the eye to drain excess fluid, Kass said.

To examine whether anti-VEGF drug injections increase risk of glaucoma, the researchers reviewed the cases of more than 800 people in British Columbia who received bevacizumab injections to treat age-related macular degeneration between 2009 and 2013.

The research team identified 74 people who wound up needing glaucoma surgery, and compared them against 740 “controls” who received the eye injections but didn’t require glaucoma surgery.

The researchers found that seven or more injections a year were associated with 2.5 times increased risk of glaucoma surgery, compared with people who received three or fewer treatments per year.

It isn’t unusual for macular degeneration patients to receive at least seven injections per year, Kass said.

But Kass added that the injections did not appear to increase a person’s overall risk of developing glaucoma by a large amount.

“[The researchers] looked for a long period of time in a whole part of western Canada and came up with 74 cases,” Kass said. “This is not exactly a common occurrence.”

The anti-VEGF drugs allow doctors to slow or halt the progression of what had been an incurable vision-destroying disease, and the new study “still doesn’t change the benefit ratio,” he said.

“These drugs are still a huge benefit to patients with the wet form of macular degeneration,” Kass said.

The study wasn’t designed to prove a cause-and-effect relationship. It only found an association between the macular degeneration treatment and the development of glaucoma.

Also, it’s not clear why the injections might cause pressure to build inside the eye, Kass said.

Repeated injections might cause trauma and inflammation that spurs pressure buildup, or the drug might interfere with the natural channels that allow fluid to seep out of the eyeball, he said.

“We think there may be something happening at the drainage system of the eye,” Eadie said. “I think that’s where most of the studies will be focused on in coming years, to figure out what’s going on.”

In the meantime, patients receiving these injections should be regularly monitored for increased eye pressure, especially if they already had glaucoma prior to treatment, Eadie and Kass said.

Source: HealthyDay

Today’s Comic

Blueberry Concentrate Improves Brain Function in Older People

Drinking concentrated blueberry juice improves brain function in older people, according to research by the University of Exeter.

In the study, healthy people aged 65-77 who drank concentrated blueberry juice every day showed improvements in cognitive function, blood flow to the brain and activation of the brain while carrying out cognitive tests.

There was also evidence suggesting improvement in working memory.

Blueberries are rich in flavonoids, which possess antioxidant and anti-inflammatory properties.

Dr Joanna Bowtell, head of Sport and Health Sciences at the University of Exeter, said: “Our cognitive function tends to decline as we get older, but previous research has shown that cognitive function is better preserved in healthy older adults with a diet rich in plant-based foods.

“In this study we have shown that with just 12 weeks of consuming 30 ml of concentrated blueberry juice every day, brain blood flow, brain activation and some aspects of working memory were improved in this group of healthy older adults.”

Of the 26 healthy adults in the study, 12 were given concentrated blueberry juice – providing the equivalent of 230 g of blueberries – once a day, while 14 received a placebo.

Before and after the 12-week period, participants took a range of cognitive tests while an MRI scanner monitored their brain function and resting brain blood flow was measured.

Compared to the placebo group, those who took the blueberry supplement showed significant increases in brain activity in brain areas related to the tests.

The study excluded anyone who said they consumed more than five portions of fruit and vegetables per day, and all participants were told to stick to their normal diet throughout.

Previous research has shown that risk of dementia is reduced by higher fruit and vegetable intake, and cognitive function is better preserved in healthy older adults with a diet rich in plant-based foods.

Flavonoids, which are abundant in plants, are likely to be an important component in causing these effects.

Source: University of Exeter

Today’s Comic

Aging and Personality: Not the Man You Used to be

Olivia Goldhill wrote . . . . .

You’re a completely different person at 14 and 77, the longest-running personality study ever has found.

Look at a photo of yourself as a teenager and, mistaken fashion choices aside, it’s likely you see traces of the same person with the same personality quirks as you are today. But whether or not you truly are the same person over a lifetime—and what that notion of personhood even means—is the subject of ongoing philosophical and psychology debate.

The longest personality study of all time, published in Psychology and Aging and recently highlighted by the British Psychological Society, suggests that over the course of a lifetime, just as your physical appearance changes and your cells are constantly replaced, your personality is also transformed beyond recognition.

The study begins with data from a 1950 survey of 1,208 14-year-olds in Scotland. Teachers were asked to use six questionnaires to rate the teenagers on six personality traits: self-confidence, perseverance, stability of moods, conscientiousness, originality, and desire to learn. Together, the results from these questionnaires were amalgamated into a rating for one trait, which was defined as “dependability.” More than six decades later, researchers tracked down 635 of the participants, and 174 agreed to repeat testing.

This time, aged 77 years old, the participants rated themselves on the six personality traits, and also nominated a close friend or relative to do the same. Overall, there was not much overlap from the questionnaires taken 63 years earlier. “Correlations suggested no significant stability of any of the 6 characteristics or their underlying factor, dependability, over the 63-year interval,” wrote the researchers. “We hypothesized that we would find evidence of personality stability over an even longer period of 63 years, but our correlations did not support this hypothesis,” they later added.

The findings were a surprise to researchers because previous personality studies, over shorter periods of time, seemed to show consistency. Studies over several decades, focusing on participants from childhood to middle age, or from middle age to older age, showed stable personality traits. But the most recent study, covering the longest period, suggests that personality stability is disrupted over time. “The longer the interval between two assessments of personality, the weaker the relationship between the two tends to be,” the researchers write. “Our results suggest that, when the interval is increased to as much as 63 years, there is hardly any relationship at all.”

Perhaps those who had impulsive character flaws as a teenager would be grateful that certain personality traits might even out later in life. But it’s disconcerting to think that your entire personality is transformed.

“Personality refers to an individual’s characteristic patterns of thought, emotion, and behavior, together with the psychological mechanisms—hidden or not—behind those patterns,” note the authors, quoting psychology professor David Funder’s definition.

If your patterns of thought, emotions, and behavior so drastically alter over the decades, can you truly be considered the same person in old age as you were as a teenager? This question ties in with broader theories about the nature of the self. For example, there is growing neuroscience research that supports the ancient Buddhist belief that our notion of a stable “self” is nothing more than an illusion.

Perhaps this won’t surprise you if you’ve had the experience of running into a very old friend from school, and found a completely different person from the child you remembered. This research suggests that, as the decades go by, your own younger self could be similarly unrecognizable.

Source: Quartz

The New Offensive on Alzheimer’s Disease: Stop It Before It Starts

Elie Dolgin wrote . . . . . .

The announcement came the day before Thanksgiving, but there was nothing in it to be thankful for: An experimental Alzheimer’s drug many thought would slow the disease’s steady cognitive decline had failed to make a significant difference in a massive trial of people with early signs of the illness.

Marty Reiswig took the news hard. “I was just sad,” he says. “I was really hopeful that it would be life-changing for us.”

Reiswig doesn’t have Alzheimer’s disease—he’s a 38-year-old real estate agent in good health. But he is part of a large extended family that’s been afflicted by Alzheimer’s for generations. His Uncle Roy died of the disease. So did Grandpa Ralph. Eleven great-aunts and great-uncles. Dozens of cousins. And now, Reiswig says, “I’ve got a 64-year-old father who’s almost dead of Alzheimer’s at this point.”His family is one of around 500 in the world with a genetic mutation that means its carriers will develop Alzheimer’s at a much younger age than those without the mutation, for whom the age of onset is typically about 80. For the Reiswigs, those with the gene become sick around their 50th birthday. Other high-risk families can start showing symptoms as early as their mid-30s or, in some cases, their late 20s.Reiswig decided not to learn his own gene status—there’s a 50-50 chance he inherited his father’s faulty DNA, and he prefers living with the uncertainty. However, he isn’t just idly waiting to meet his fate.

Three years ago, he signed up for an innovative drug study that could alter his family’s genetic destiny. Once a month, a nurse comes to his home, inserts a needle in his arm and watches as a bag full of liquid slowly drips into his bloodstream.As with most trials designed to test whether an experimental drug works—even for diseases that are akin to death sentences—Reiswig might be getting a placebo. But there’s also a chance his monthly infusions include a drug that could stop him, his family members and others like them from losing loved ones to Alzheimer’s. Or, at the very least, delay the disease long enough to give them many more good years, genetics be damned.The key is early intervention, before symptoms are evident and brain damage is too extensive. “That’s how you stop the disease,” says Rudy Tanzi, director of the Genetics and Aging Research Unit at Massachusetts General Hospital. “You don’t wait.”

Some families carry a genetic mutation that means they will develop Alzheimer’s at a young age. High risk families can start showing symptoms as early as their late 20s.

Push Back the Onslaught

This aggressive attempt to prevent Alzheimer’s rather than treating it is the most exciting new development in decades, as well as a radical departure for researchers and the pharmaceutical industry. Traditionally, drug companies have tested their therapies on patients who already have memory loss, trouble thinking and other signs of dementia. It’s been a losing tactic: More than 99 percent of all Alzheimer’s drugs have failed tests in the clinic, and the few that have made it to the market only ameliorate some symptoms. Not a single medicine has been shown to slow the relentless progression of the disease.

But with this new approach, even partial success—an appreciable slowing of brain degeneration—could have a big impact, says Dr. Reisa Sperling, a neurologist who directs the Center for Alzheimer’s Research and Treatment at Boston’s Brigham and Women’s Hospital. If a drug therapy can push back the onslaught of dementia by five or 10 years, she says, “many more people would die of ballroom dancing instead of in nursing homes.”

It’s a strategy being tested in five big clinical trials that collectively will cost anywhere from $500 million to a whopping $1 billion. But prevention advocates are confident these studies are a worthwhile gamble. “It sometimes doesn’t feel like it, because we see failure after failure, but we have made huge progress” in learning from mistakes and designing better trials, says Stacie Weninger, executive director of the F-Prime Biomedical Research Initiative and co-chair of the Collaboration for Alzheimer’s Prevention, a coalition of leading prevention researchers. “I’m more hopeful now than I’ve ever been that we can stop this disease.”

If drug therapy can push back the onslaught of Alzheimer’s by five to 10 years, many more people could avoid such an agonizing end.

Success in one or more of these trials matters not only because they may save the lives of the Reiswigs and for many older Americans; they may also save our health care system. Dementia is the most expensive disease to care for, and the number of patients with the condition is expected to explode in the coming years.

Part of the problem with past efforts to tackle Alzheimer’s was that therapies were tested on many people who didn’t even have the disease, because the only definitive way to diagnose Alzheimer’s was through a brain autopsy. That postmortem could reveal the hallmark signs of the disease, but while a person is alive, doctors could make only a best-guess diagnosis—and they were often wrong. That meant Alzheimer’s trials were filled with people who had other types of dementia and were never going to benefit from the therapies. In hindsight, it’s painfully clear the studies were set up to fail.

The past five years have brought two powerful diagnostic tools that help ensure Alzheimer’s therapies are now being given only to Alzheimer’s patients. One involves a kind of brain scan known as positron emission tomography, or PET, while the other requires a spinal tap. Both test for the presence of the toxic amyloid protein that forms the sticky brain plaques thought to be responsible for the disease. “Now, with the right tools, we can match the patient population to the anti-amyloid therapies,” says James Hendrix, director of global science initiatives at the Alzheimer’s Association.

That’s what pharmaceutical company Eli Lilly did in its latest trial of solanezumab, the drug whose trial failure before Thanksgiving had so saddened Reiswig. Lilly had previously tested solanezumab in two huge studies, each involving more than 1,000 presumed Alzheimer’s patients. After those trials ended in failure, however, the company conducted PET scans and realized that up to one-third of its study subjects didn’t have the disease. So Lilly tried again with only people who had confirmed amyloid in their brains. The company also focused on only those with mild forms of the disease. Alas, the third trial was a flop too.

Maybe solanezumab is a bad drug. However, in the trials it did target amyloid as it was supposed to, and it modestly outperformed a placebo by a range of cognitive and functional measures in clinical testing, even if it didn’t meet the threshold needed for marketing approval. That’s why Sperling and others are holding out hope for another explanation: that solanezumab was simply given too far along in the disease process, after irreparable harm has already occurred in the brain. If that’s the case, it might prove more useful if given sooner.

“I’m afraid that even by the stage of very mild dementia, you’ve already lost 70 percent of the key neurons in the memory regions of the brain,” Sperling says. “Ultimately, we need to start treating people before there are symptoms.”

Researchers now know that amyloid starts to accumulate in the brain at least a decade or two before the onset of cognitive problems. This stage of the disease is referred to by experts as “pre-clinical Alzheimer’s,” although few people who qualify for this diagnostic label realize they have a problem. Dr. Jason Karlawish, a geriatrician who co-directs the University of Pennsylvania’s Memory Center, describes this as a “real conceptual shift” in our understanding of the disease. “Someday, you won’t have to be demented to be diagnosed with Alzheimer’s disease,” he says.

What’s happening in this early stage of Alzheimer’s can be likened to the kindling that starts a house fire. Amyloid plaques slowly smolder for years, consuming the neuronal tinder in our brains. By the time dementia kicks in, the fire is raging and it’s too late to save the house. Calling in firefighters at that point is a waste of time and money. You need to dial 911 at the first signs of smoke—and the same could be true of when to deliver anti-amyloid drug therapies.

Hundreds of Billions Lost

Three of the five prevention trials are giving drugs to elderly individuals who are still cognitively normal but have a high chance of developing Alzheimer’s, either because of elevated amyloid levels in their brains or because they inherited a risk-factor gene called APOE4. In either case, the disease is by no means a foregone conclusion for these subjects.

Not so in the other two studies, which focus on those rare kin groups in which doctors know with certainty, because of gene testing, who will develop Alzheimer’s in each family and at roughly what age. One such trial, led by the Banner Alzheimer’s Institute in Phoenix, is being done in Colombia because it includes the world’s largest known family with a mutation that triggers early Alzheimer’s disease. The second study, run by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) of Washington University in St. Louis, includes the Reiswigs and more than 50 other families like them.

“For us, the hope is that we’re going to stave off the damage and delay the onset of symptoms,” says Reiswig’s second cousin Brian Whitney, who knows he carries his family’s Alzheimer’s mutation. At 44, he will soon develop Alzheimer’s if the therapy he’s receiving doesn’t work. His hope for a long life hinges on DIAN-TU.DIAN-TU’s is a two-in-one study that’s testing a pair of different experimental therapies for their ability to keep Alzheimer’s at bay. Participants don’t know if their getting a placebo or not, but they know which of the two drugs they are receiving otherwise. For Whitney, it’s a Roche drug called gantenerumab, and in Reiswig’s case, it’s Eli Lilly’s solanezumab. Both drugs target the amyloid protein behind Alzheimer’s but do so in different ways: Roche’s gantenerumab breaks up the amyloid plaques that can spur neuron death; Eli Lilly’s solanezumab leaves plaques alone but can mop up free-floating protein to prevent further plaque formation.

Solanezumab thus operates like an outreach counselor who helps take crime-prone youth off the streets of a graffiti-filled neighborhood. If the kids aren’t left to form gangs, they won’t vandalize the area any further. The drug, by eliminating scattered amyloid, stops the deviant proteins from clumping together and forming additional brain-destroying plaques.

That’s the idea, but researchers don’t yet know whether a drug that has failed time and again as a treatment for Alzheimer’s can prevent it. Some experts remain skeptical. They argue that further studies on anti-amyloid drugs are a waste when what is really needed are new therapeutic strategies—and that anyone who still sees promise in solanezumab because it beat a placebo by some tiny amount is guilty of spin and wishful thinking.

“We’re treating asymptomatic people with a drug that has no evidence whatsoever of efficacy,” says Peter Davies, a neuroscientist who directs the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at the Feinstein Institute for Medical Research. “You might as well give them aspirin.”

But the federal government clearly thinks the trials are worthwhile. In addition to funding from drug companies and philanthropies, taxpayers are ponying up tens of millions of dollars for these trials as part of the country’s national plan to effectively prevent or treat Alzheimer’s by 2025.

The consequences of failure could be dire. Approximately 5.4 million Americans suffer from Alzheimer’s, and if no disease-delaying therapies are found soon, that number is expected to nearly triple by 2050, at which point the cost of treating and caring for all those people could top $2 trillion per year, after adjusting for inflation. That’s up from $236 billion today. One in every five Medicare dollars is now spent on people with Alzheimer’s and other dementias. In 2050, it will be one in every three dollars. And those figures don’t even include the hundreds of billions more in lost wages for family members who take time away from their jobs to care for loved ones. It’s not a question of a day off now and again. People with Alzheimer’s require around-the-clock care—and more than one-third of all dementia caregivers develop clinical depression.

As Gregory Petsko, director of the Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine in New York City, says, “Pretty much every family is going to have a relative affected by Alzheimer’s, and that’s going to change the way we live, the way we think, the way we plan for our future—everything.”

‘I Can’t Forget Your Face’

Dr. Randall Bateman had no warning the latest solanezumab trial was going to be a failure. He was racing around the house doing chores in anticipation of a big family dinner last Thanksgiving when he received an early-morning phone call on November 23 from executives at Eli Lilly. “I was extremely disappointed,” says Bateman, who leads DIAN-TU. “But I wouldn’t say it was surprising.” He’d been saying prevention has a better shot of success than treatment for years.

Another leading prevention proponent is Dr. Paul Aisen, a neurologist who directs the Alzheimer’s Therapeutic Research Institute at the University of Southern California. In 2014, Aisen teamed up with Sperling for a 1,150-person trial called A4. Short for Anti-Amyloid Treatment in Asymptomatic Alzheimer’s, A4 tests solanezumab for prevention. The drug is given to seniors who have no signs of dementia but do have elevated amyloid levels, as measured by a PET scan of the brain. It is looking for changes over a 39-month period in cognitive function, self-care abilities, brain tissue health and other indicators of Alzheimer’s. “We still need to find out what the benefits and risks are” in patients not yet showing symptoms, Aisen says.

The trial asks a lot of its participants. A4 subjects must be willing to come to a hospital once a month for more than three years to receive infusions containing an unproven medicine for a disease they don’t have and might not get. There’s no guarantee of benefit or even safety. And the trial is not particularly remunerative. Some participants can receive up to $2,480 if they complete all the study protocols, including two PET scans, four MRI scans, two spinal taps and 42 infusion visits. But many do not get any compensation, unless you count parking validation.

None of that dissuaded Jerry Blackerby from taking part in A4. “With my family history, I have expected to have Alzheimer’s long before death, and I haven’t yet,” says Blackerby, 82, a retired technical writer whose mother died from the disease, as did her three siblings. “If I’m going to have it, I want to be involved in the study to try to keep others, especially my descendants, from having to go through the hell I’ve seen family members go through.”

Last December, Blackerby drove more than 100 miles from his home in southern Oklahoma to the University of Texas Southwestern Medical Center in Dallas to receive his first infusion. He will make this same four-hour round-trip trek every month for the next three years.For Don, a retired insurance agent, the motivation to participate in A4 was his partner, Fran. He first noticed her Alzheimer’s four years ago when he arrived at her house expecting a dinner of meat stew, only to find a near-empty pot. “She had remembered the onions,” he recalls. “But she had forgotten everything else.”

Don (who asked that his last name not be used because he didn’t want to come across as self-promotional) tried to enroll Fran in A4, but her disease was too far advanced. Only he was eligible—a PET scan showed he had the hallmark amyloid logjam in his brain. He started getting infusions last fall at Brigham and Women’s Hospital in Boston.

On a rainy day in late November, Don, with a plaid-blue shirt sleeve rolled up past the elbow and an IV catheter in his right arm, reminisced about meeting Fran nine years ago at a singles dance at Vincent’s Nightclub in the suburbs south of Boston. He’s mild-mannered and surprisingly youthful for a 76-year-old, gray-haired grandfather who raised six children on his own after his wife died in a car crash 33 years ago. He beams when he talks about Fran retaining her sense of humor and ability to play tennis, but he turns solemn when he describes how it took four tries to explain to her why he was going to the hospital today. “She knows,” he says, “but she forgets.”

While he’s talking, a nurse comes to deliver the saline flush that always follows Don’s infusion. She introduces herself, although Don recognizes her from a previous visit. “I can’t forget your face,” he says. “I told you, ‘You look just like my cousin.’”

The amyloid in Don’s brain has clearly not impaired his memory, but it’s there. And perhaps the therapy he is receiving will halt further damage. Or perhaps he will suffer the same fate as Fran. “I worry for myself. I worry for my kids. But I try not to think too much about that,” he says. “Right now, I have too many obligations.”

Good Genes in NorwayAisen, the A4 investigator, is optimistic about solanezumab as a preventive medicine. In announcing the failure of the drug for symptomatic Alzheimer’s at a major scientific meeting late last year, he told a room full of doctors, neuroscientists and drug executives, “I expect the treatment effect to be larger in an earlier stage of disease.” Results of the A4 study will be known in 2020.

Until then, Eli Lilly is continuing to support A4 and DIAN-TU, the two prevention trials that include solanezumab, but the company has already signaled that it plans to focus on other therapies. Many academics in prevention research are beginning to consider other drugs too. They are still committed to prevention; they just want to determine which of the anti-amyloid drugs works best.Last December, Bateman and his collaborators announced they were adding a third drug to the DIAN-TU study, one that blocks the beta-secretase enzyme responsible for producing amyloid. Also, Aisen and Sperling recently launched a huge prevention trial, called EARLY, which is administering that same beta-secretase-targeted drug to people who, as in A4, are healthy but have elevated amyloid in their brains.

Just this month, a late-stage trial of a different beta-secretase inhibitor, one from Merck, was halted early after experts determined that the drug had no chance of helping Alzheimer’s patients who already showed symptoms of the disease. Dr. Roy Twyman, head of Alzheimer’s drug development at Janssen, a division of Johnson & Johnson and the manufacturer of the beta-secretase inhibitor in the EARLY and DIAN-TU trials, is confident that prevention with this type of agent should work, and he points to a study from Iceland as evidence that the strategy should work. Five years ago, researchers there discovered the first known gene mutation that protects individuals against Alzheimer’s. It’s extremely rare, found in less than one in 200 people from Nordic countries. Yet those who carry the mutation are about five times more likely to reach their 85th birthday dementia-free.

And what does that mutation do? It impairs the ability of beta-secretase to do its job. “Nature has already taught us a lesson in humans,” says Twyman—and it’s one that J&J hopes to take to the pharmacy shelf.

Another beta-secretase inhibitor, from Novartis, is one of two drugs included in a prevention study, the Generation trial, run by Dr. Eric Reiman and his colleagues at the Banner Alzheimer’s Institute. That study, like A4 and EARLY, is being done with cognitively normal older adults at risk of developing Alzheimer’s. But rather than looking for signs of amyloid accumulation, the Generation trial involves volunteers who inherited two copies of APOE4. That increases their odds of developing Alzheimer’s about fifteenfold, compared with the general population.An estimated 2 percent of the population has two copies of APOE4, but few in that select group know it. It hasn’t been worth getting tested for this gene because there was little you could do with the results. “Really, for the first time, what to do about it is different,” says Dr. Pierre Tariot, the Banner Alzheimer’s Institute’s director. “You can choose to participate in a trial.”

What Do You Mean I’m Not Covered?

If the drugs prove to be effective at preventing Alzheimer’s, their success will immediately raise another urgent question: Who’s going to pay for them?

Prevention proponents envision a day in which everyone above a certain age—say, 50—would get screened regularly for molecular and genetic risk factors for Alzheimer’s. If they test positive, they could start taking a preventive medicine, much as those with high cholesterol today can pop a daily statin to ward off a heart disease. “We will eventually think about treating a much broader population,” says Sperling.

But statins cost pennies a pill. Any new Alzheimer’s drug would likely cost tens of thousands of dollars per year. Insurance companies may balk at paying that for seemingly healthy individuals, especially because not everyone with elevated amyloid or APOE4 will develop dementia.

Howard Fillit, chief science officer of the Alzheimer’s Drug Discovery Foundation, thinks researchers should focus on treating people with symptoms but halting the disease at the pre-dementia stage when only mild cognitive impairment is evident. Problems with memory, thinking and judgment at that point are more pronounced than for those who experience normal, age-related “senior moments.” But most people with MCI are not so far gone that they require constant care. They can keep living independently.

“MCI is the sweet spot in terms of the cost of trials, the cost of drugs and quality of life for patients,” Fillit says. “That’s still prevention because you’re preventing dementia.”

Anyone who’s ever had a spouse get lost coming home from the grocery store or a parent unable to write a check might disagree. And so many researchers continue to dream of a time when they can prevent all cognitive impairment. To that end, they plan to start testing drugs even earlier in the disease process, before any amyloid has started to damage the brain. For example, Aisen and Sperling will soon launch a placebo-controlled trial involving people who weren’t eligible for the A4 or EARLY trials because their amyloid levels didn’t reach the threshold for inclusion. And Dr. Eric McDade, a neurologist involved with DIAN-TU, plans to start treating people with the sure-thing, genetic form of Alzheimer’s—families like the Reiswigs and others—even sooner than the current trials allow. “Going as early as possible is really the goal,” McDade says.

Developing drugs to prevent Alzheimer’s disease could be a discovery of Nobel proportions. There is no guarantee the current trials will succeed, but researchers believe they are getting close to solving what had, until recently, seemed to be one of medical research’s toughest challenges.“It’s an exciting time for us,” says the Banner Alzheimer’s Institute’s Reiman. “The hope is that we already have a treatment that can substantially reduce the risk of Alzheimer’s. But there’s only one way to find out, and that’s through these trials that chart new territory.”

Source: Newsweek