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Kristin Murphy, Deseret News
Dr. Norman L. Foster, Center for Alzheimer's Care, Imaging and Research director, shows what parts of the brain correspond to an amyloid PET scan showing Alzheimer's plaque pathology in a patient with memory loss at the University of Utah's Center for Alzheimer's Care, Imaging and Research in Salt Lake City on Tuesday, June 18, 2019.

SALT LAKE CITY — The last drug approved to treat Alzheimer's disease went on sale in 2003, and a handful of highly anticipated and promising phase-three clinical trials for other drug treatments recently bombed. The road to a cure for Alzheimer's is lined with bruised drug companies — and now, some big players have abandoned it completely.

It's been a discouraging year in a remarkably rough search for elusive drug treatments or a hoped-for cure for the devastating neurological disease, which impacts roughly 5.8 million Americans and their families. The national Alzheimer's Association estimates the cost of Alzheimer's and other dementias will approach $290 billion in 2019.

"It's been pretty dismal. We've had nothing but failed clinical trials since 2003, which is why companies see this as a black hole and therefore pull out. And of course we are concerned that if all the companies pull out, we will never get a treatment," said neurologist Dr. R. Scott Turner, professor and director of the Memory Disorders Program at Georgetown University.

Doctors, researchers and others have for decades predicted that a cure was just over the horizon. Now they're not so sure, and some worry about the impact of failed clinical trials — expensive even when they succeed — on investment in drug development.

Joseph Tolman

Pfizer is the largest company to abandon Alzheimer's research completely, announcing in late 2017 it would no longer try to develop treatments for neurological diseases, instead increasing focus on cancer therapies. Merck halted clinical research on a potential treatment after tests found subjects' cognition slightly worse on the trial drug compared to a placebo.

Biogen, Roche and Eli Lilly are among drug companies still looking despite the failure of clinical studies to yield positive results.

What happens if drug companies lose their appetite for Alzheimer's studies? Dr. Dylan Wint, neurologist and psychiatrist specializing in neurodegenerative diseases at Cleveland Clinic's Lou Ruvo Center for Brain Health in Las Vegas, said, "If you are studying therapeutics, I think the exit of drug manufacturers is a huge deal, because they drive research into therapies."

Others say maybe it won't matter that much, and point out that other sources of funding, including government grants, haven't dried up. They also note that in spite of a cure remaining elusive, the information gained so far from research is making a difference. Ideas about how to help Alzheimer's sufferers have already begun to make a striking pivot toward prevention and managing the disease as a chronic illness.

"I am actually more optimistic than I was a couple of years ago," said Dr. Norman L. Foster, professor of neurology, director of the Center for Alzheimer's Care, Imaging and Research, and senior investigator for the Brain institute, all at the University of Utah. "I think we are beginning to make significant strides," he added, when it comes to understanding how best to conduct studies and choose targets.

Fears and funding

Salt Lake dentist Morgan Smith's interest in Alzheimer's disease is not academic. His paternal grandmother had the disease for 14 years before her death. And his mother, Bonnie Smith, was diagnosed a couple of years ago but recently suffered a decline so steep that his dad, Steven, can no longer care for her at home.

Like most children of those with Alzheimer's, the younger Smith wonders about his risk of getting Alzheimer's, which robs people first of memories and skills, then language and connection to loved ones.

Kristin Murphy, Deseret News
Dr. Norman L. Foster, Center for Alzheimer's Care, Imaging and Research director, poses for a portrait at the University of Utah's Center for Alzheimer's Care, Imaging and Research in Salt Lake City on Tuesday, June 18, 2019.

It's a fear Jocelyn Steward of Smyrna, Georgia, knows well. Her mother's decline came with high drama: Odessa, now 78, drove her car into a neighbor's pool, among other misadventures. She uses a wheelchair, can't brush her teeth or wash her own face and needs to be reminded to chew her food.

"The most distressing is the vocalization. She calls for my dad constantly if he isn't in the room. She sees something on TV and interjects that into her life," said Steward. If her mom sees a shoe ad on TV, she'll lament, "I don't have any shoes. Where are my shoes? It goes on for hours. She cries, 'Lord help me. Jesus help me.'"

Steward, youngest of Odessa's four children, once timed her mom's repetition: six hours.

Family members and friends of those with Alzheimer's are deeply affected by the disease, and deeply concerned about funding for ongoing research. Even big donors to fundraising efforts for research, including those of the national Alzheimer's Association, often cite a personal connection to explain their donations.

The association's nearly 40-year effort has put it on the front lines of paying for discovery science, early detection, treatment and prevention research, said Dr. Rebecca Edelmayer, director of scientific engagement for the Alzheimer's Association.

The group has poured more than $165 million into 450 scientific projects in 25 countries, from "bench to bedside" as they call the journey from early lab work to treating patients, she said. They also have 34 ongoing trials as part of the "Part the Cloud" program to accelerate the research process.

Edelmayer said the association's grant program helps fund not only academic researchers and startups working in drug development, but also contributes to lifestyle interventions and some clinical trials, sharing some costs with drug companies.

That role could be increasingly important if other pharmaceutical companies give up on drug development for Alzheimer's.

Other funding streams also remain. The National Institutes of Health recently received a financial windfall of federal funds for Alzheimer's research, Turner said. But NIH funds can be used for basic science and animal work — not for clinical trials needed to find, test and prove a drug.

Research wins

Wint, of the Cleveland Clinic, isn't sad to see the focus of research shift from developing drug therapies for patients who already have serious symptoms to trying to prevent Alzheimer's — or at least impact it earlier. Treatments that stabilize patients or prevent disease would be welcome, he said. A cure is not the only worthy goal.

And even without that big "Eureka" discovery, there have been gains from the war on Alzheimer's, including the ability to diagnose with near-total accuracy, said Foster, of the University of Utah. "We can tell who has Alzheimer's and who has something else. And it's now possible to decrease individual risk by good medical management and to prevent crises by supporting families.

Kristin Murphy, Deseret News
Binders of Alzheimer's research material at the University of Utah's Center for Alzheimer's Care, Imaging and Research in Salt Lake City on Tuesday, June 18, 2019.

"These are all things we can do simultaneously. It's not 'cure or nothing.' This is a chronic disease and we have to have a chronic disease approach," he said.

Studies have revealed many insights, including two proteins considered significant. Beta amyloid builds up in the brain, creating plaques believed to interfere with how neurons communicate. Tau protein forms "tangles." But neither mechanism is well-defined, and reaching conclusions is complicated by the fact that some people have amyloid buildup without losing cognition, while others have decreased cognition and no amyloid. Plus, researchers can create Alzheimer's-like impact in the brains of mice and then clear it out. But that hasn't worked in human brains.

Still, in addition to the two proteins, several risk factors for cognitive impairment have been identified, including vascular problems, inadequate sleep, stroke, smoking, sedentary lifestyle, low education, social isolation, brain injury and more.

Heredity seems a relatively small risk factor, with the exception of a few genes known to significantly increase risk. Turner said the most common risk-factor gene, APOE E-4, increases the likelihood of Alzheimer's, but doesn't convey certainty.

Treatments of the future

These insights are changing who medical professionals target for Alzheimer's treatment.

"There's a theory that we're treating too late in the disease," said Foster. "It's looking more and more that the brain is resilient or resistant to the plaque changes for some period of time, but then resistance is overcome and the patient goes down. We know from following patients that those with mild cognitive impairment due to Alzheimer's pathology can go on for quite a while without much change."

Those with dementia are already in progressive decline, with options for effective therapy less likely, he said.

Researchers and clinicians predict that future effective treatment will focus instead of prevention, following what Turner calls a "statin model." He's referring to the decadeslong practice of prescribing statins to reduce blood pressure and prevent heart attacks and strokes.

Kristin Murphy, Deseret News
Dr. Norman L. Foster, Center for Alzheimer's Care, Imaging and Research director, shows what parts of the brain correspond to an amyloid PET scan at the University of Utah's Center for Alzheimer's Care, Imaging and Research in Salt Lake City on Tuesday, June 18, 2019.

"This is a disease that starts well before we see any clinical symptoms," Susan Resnick of the National Institute on Aging told reporters during a National Press Foundation fellowship program in Washington, D.C., in May.

The trick is figuring out how to identify people who seem normal "but we think are going to get Alzheimer's, then deciding on the treatment."

Researchers are also considering lessons from the search to subdue HIV/AIDs, which always killed patients until a combination-drug treatment was discovered. "One drug did nothing. But put two or three together and — boom!" said Turner. "HIV was no longer fatal. It became another chronic, manageable disease like high blood pressure or diabetes."

He added, "Doctors cure very little, but they manage a lot."

Managing risks

What's good for the heart is good for the brain, inspiring much of the advice experts now offer for avoiding Alzheimer's: Get aerobic exercise. Control your blood pressure and blood sugar. Don't smoke. Avoid excessive alcohol.

Turner said it's never too late to make those changes.

"We don't know the extent to which each risk factor will impact an individual's likelihood of getting Alzheimer's," said Wint. "You have your own set of risk factors and I have my set. ... We do know there are multiple risks."

Other modifiable risk factors include sleep, diet, maintaining mental activity and social connections, among others.

For John E. Lewis, a longtime Alzheimer's researcher who left the University of Miami to start a supplement and nutrition company, Nurish.Me LLC, the link to diet is indisputable. "The focus of any research campaign on brain health at this point ought to be in addressing how lifestyle factors such as nutrition and exercise will keep the vast majority of people healthy and well," said Lewis, who touts his company's supplements.

"A small percentage of people may still get sick due to genetics, chemical exposure and other environmental factors, and those areas can continue to be priorities for funding where we still need answers. Meanwhile, we already know that a predominantly whole-food, plant-based diet, certainly key nutrients that likely cannot be gotten only from food, and daily exercise are the keys to preventing disease and in some cases even reversing it."

With so many options, the Alzheimer's Association hopes to help the public "be savvy about the research they consume," said Edelmayer. It publishes evidence-based recommendations such as 10 ways to love your brain, including "habits people could use to potentially reduce risk."

When worried but symptomless children of Alzheimer's patients ask Wint for advice, he offers this: "We don't know how important your risk will be compared to all the things we can control. Let's control the things we can. We leave it to the scientists to figure out ways to combat what we can't."

Steward, 41, has a degree in cellular biology and a doctorate in health services administration. She avidly tracks Alzheimer's news. And she's changed some of her habits. She is learning new things, starting her own business and taking art classes. She doesn't watch a lot of TV or play games on her phone. Her diet is mostly plant-based.

Steward family photo
Jocelyn Steward of Smyrna, Georgia, and her mom, Odessa, who has Alzheimer's disease. Besides helping her dad, James, care for Odessa, Jocelyn worries that she will eventually have the disease herself.

Smith, the dentist, 40, changed his dietary habits, too. He's always paid attention to his sleep, but doesn't always get what he thinks he should. For exercise, he plays basketball, jogs, mountain bikes and swims.

Wint, like every expert consulted for this story, sees great value in early diagnosis. Gone are the days of thinking, "There's no cure, so why bother finding out? You can't do anything anyway," he said.

Many things can impair cognition, including medication, health conditions, hormone and vitamin deficiencies and more. There are also ways to improve cognitive status. Slowing cognitive decline may buy time for a cure or treatment to be found.

Other benefits of early detection are better care and access to clinical trials.

"We have a lot to be hopeful about," said Wint. "I can't say for sure whether the drugs were failures ... it was kind of strange, given what we know, to start out with the premise amyloid was fully responsible for cognitive decline." It's possible they tackled one disease factor like amyloid buildup, while leaving other contributing factors in place, he noted.

Turner sees other promising research options, but any effort will require more people to volunteer for studies. "We never get enough people volunteering. We can have fantastic studies, but if nobody joins, we don't learn anything."

Steward family photo
Jocelyn Steward of Smyrna, Georgia, shares caregiver duties with her dad since her mom, Odessa, has Alzheimer's disease. It's a challenge because her folks live more than two hours away.
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And not all drug companies have given up. "There are methods the drug companies are using to try to reduce their financial exposure," like teaming up on clinical trials in order to share risk, Foster pointed out.

And failing to find a cure might keep drug companies invested, Foster said, because a cure isn't as advantageous to them as "something you have to keep taking for the rest of your life."

An ongoing drug treatment would reap rewards for drug companies, and will likely keep some companies engaged in research, he said.