UW Researchers Break Ground with Alzheimer's Study 2015

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VOL. 40 NO. 29

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MADISON, WISCONSIN

UW researchers break ground with Alzheimer’s study

JAMES HEIMER

n COVER STORY

UW researchers break ground with Alzheimer’s study

JAMES HEIMER

BY DENISE THORNTON

ISTHMUS.COM JULY 23–29, 2015

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eanne Bristol and Kay Cronin remember their dad as a proud man who worked hard to get ahead. “He put himself through college in his 50s,” Kay says. “It was important to him.”

A father of 11, Jerome Coonen was energetic, curious and a jack of all trades. He worked as a grocer and a baker before completing his degree and teaching high school science. After that, he ran his own hydraulics repair shop. “He was always learning something,” says Kay. “Always reading.”

But in 1992, Coonen began to slip.

One day, he got lost driving home from a visit with his son, who lived just a mile and a half away.

“He became more and more confused, but he made a lot of good decisions,” Kay remembers. “He decided to sell his car. But then he began to call us in the middle of the night. ‘There’s a kitty in my room.’ ‘There’s bugs on the ceiling.’ We knew he needed to be in a place with overnight staff.”

They would soon discover their father suffered from a disease called Alzheimer’s, which afflicts an estimated 5 million Americans. Until he could get into a facility, his children took turns spending the night with him. “When he was moved, it was easier for us. He was a sociable person and enjoyed having staff to talk to at night,” Kay says. In the nursing home, things seemed better for a while, but during her regular visits, Kay witnessed her dad’s confusion deepen until the end.

Jerome Coonen is remembered by his daughters as an intellectually curious man.

It was painful to watch a once sharp man slowly lose himself. Now Kay and Jeanne fear a similar fate could await them. Not only did their father die from the disease, so did both of their grandfathers. Will they be next?

One in three seniors die with Alzheimer’s or another type of dementia, according to the Alzheimer’s Association. It is the only cause of death among the top 10 in America that cannot be prevented, cured or even slowed, and very few families have avoided the long goodbye between victims and their loved ones.

Like millions of others, the sisters watched a loved one’s memory and personality slip away before their eyes. But unlike most people, Jeanne, Kay, and their sisters Grace and Nancy have been given a chance to do something about this insidious and frightening disease.

“Grace saw an item in the paper,” says Jeanne.

“It was a study looking for people with a parent who had Alzheimer’s.” Grace is a nurse, Jeanne added. “She...said they needed us.”

The sisters were ideal candidates for the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a study trying to unlock the mysteries of why some people get Alzheimer’s and some don’t. People with a parent who had Alzheimer’s are about three times more likely to get the disease than those with no family history.

To help researchers get a better understanding of the disease, both Bristol, who lives in Balsam Lake, and Cronin, who lives in Kaukauna, have been driving every other year to UW Hospitals in Madison, where they’ve submitted to numerous tests and grueling brain teasers. The two are part of a massive study that has gone

on for almost 15 years. It’s one of a number of studies that is putting the UW in the vanguard of Alzheimer’s research.

Neither sister cares to dwell on the possibility that one of the tests might reveal early symptoms of Alzheimer’s. “They might say they see something in your brain,” says Jeanne. “You know that not everyone is going to get that call, but if they do say they have seen something in my brain, I’ll just keep it active. That’s all you can do.”

DR. MARK SAGER TRACES THE STUDY BACK TO AN “ah-ha moment” he had in 2000 over a glass of wine with his wife. Sager, who until his recent retirement was professor of medicine at UW School of Medicine and Public Health, was telling his wife about the need for more Alzheimer’s research.

“It was her idea,” he says. “She said, ‘You need to study people like me,’” meaning people who don’t have the disease. Sager decided to study not just people who don’t have the disease, but “people who are at higher risk of the disease because of their family history so that clues can be found before someone becomes symptomatic.”

Alzheimer’s is a slow disease that is present in the brain long before it can be detected using current methods. It is thought to advance through three stages — an early stage with no symptoms, a middle stage when people have increasing problems with memory or other thinking skills but are still functional, and the final stage of severe dementia that ends in death. The hope is to come up with treatments that stop the disease before symptoms begin, or at least before they worsen to the final stage.

gib’s bar presents:

sunday, august 2 dj and appetizers Sisters Kay Cronin (left) and Jeanne Bristol lost their father and both grandfathers to Alzheimer’s. They’re now volunteers in a massive study that hopes to identify who is at risk for the disease.

“If they do say they have seen something in my brain, I’ll just keep active.”

— Jeanne Bristol

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JULY 23–29, 2015 ISTHMUS.COM

“There was no preclinical research being done before we began,” Sager says. “All studies were being done on people who clearly had Alzheimer’s.

Here in Madison, we took a risk with a new direction, and it panned out.”

There aren’t a lot of risk takers among those who fund research at the federal or state levels. Sager’s team was fortunate. “We found funders, and we got support here from the Medical School,” Sager says. Today, preclinical research like Sager’s study is what Madison is best known for in the Alzheimer’s world.

The question researchers are probing is who is at risk.

“We knew family history was a risk factor, and we announced on television that we were starting this study,” says Sager. “Within 24 hours we had 600 calls. The public engagement has been the most amazing thing about this.”

Most studies are not this big because it takes a lot of money to identify and recruit appropriate people for such a large-scale test. The number of participants is part of what makes this study so promising.

“It’s huge,” says Sager. “Perhaps 10% of the population has an abnormal memory test. If you only have 250 people in a study, that’s only 25 people. But if you have 1,500 people, you have 150 examples, so you can say something definitive about what you are finding.”

The Wisconsin Registry for Alzheimer’s Prevention began to enroll subjects in 2001 and is following over 1,500 people, including 1,100 who have a family history of Alzheimer’s and 400 who do not. That makes it the largest and longest-running study of its kind in the world.

The study compiles a wide range of information on participants, including their background, medical history and lifestyle, including exercise and diet. Researchers collect vital signs, record brain images and take samples of cerebral spinal fluid to look for biomarkers that may have predictive value long before the disease expresses itself. Blood samples are also collected to look for genetic risk factors.

For many volunteers, the most grueling part of the process is a battery of cognitive tests to check memory, attention and other mental skills. Understandably, children of Alzheimer’s victims often worry that their memory is failing.

By design, the tests are not reassuring. “They are designed to make sure you fail,” says Bruce Hermann, a professor of neurology and director of the Charles Matthews Neuropsychology Lab at the UW School of Medicine and Public Health. He assembled the test battery from well-known standardized cognitive tests into a formidable mental challenge that almost everyone dreads.

Researchers need to know where test subjects fall within a broad population range, and test scores can

sunday, september 6

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n COVER STORY bounce around. It is the trend over years of testing that is telling. If someone were to get a perfect score, there would be no room for them to do better, so Hermann made sure that a perfect score is impossible.

These kinds of stressors have not stopped people from lining up for the program. The willingness of the volunteers to keep coming back is part of what makes this a groundbreaking study, providing a rare look into how brains change over time.

“Our participants are dedicated and passionately supportive of the project,” Sager says. “They have made our job so much easier,” he adds, noting that while the program spends money each year on memory testing and neural imaging, it does not spend funds on recruiting.

“People are still calling us to be part of the study because they’ve seen what Alzheimer’s has done to their family members.”

“The cohort has really hung in there.

They volunteer to get lumbar punctures.

They are signing up to donate their brains.”

“The public engagement has been the most amazing thing about this.”

— Dr. M ­ ark Sager

ISTHMUS.COM JULY 23–29, 2015

But as the research study itself ages, there are some challenges. Some of the participants have moved since they signed up. They are now scattered to 28 states and Canada.

“Participants are starting to retire and go to warmer climates,” says Hermann.

“We hope they will come back and remain as involved as they have been.”

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KAY AND JEANNE NOW SPEND THEIR winters in Arizona, but they intend to keep coming for their test appointments, even though they’re retired. They have also agreed to donate their brains after they die to the program for analysis.

“The post-mortem brains will be very valuable to the study,” says Sager. “We will be able to connect any pathology in the brain with the subject’s history of cognitive change and lifestyle that has been collected for several decades.”

Jeanne, who was a computer programmer and systems analyst, and Kay, who worked in food service and child care,

usually come to Madison the day before testing, so they’re well rested for the long day.

After a day of blood draws and another round of tough cognitive testing, Jeanne and Kay reflected on what participating in the study means to them before the long drive home.

“I’ve learned a lot in this process,” says Kay, who is 73. “In my 30s, I weighed 230 pounds. I have worked to keep it off, and I’m glad I did. Staying fit is important. I walk now, here, there and everywhere. You have to keep yourself moving. You have to keep your mind alert.”

Both sisters play cards regularly, and they both volunteer through AARP to help seniors with their taxes.

“It can be scary,” admits Jeanne, 75.

“And it would be even scarier to be told the anomalies in the brain are increasing.

They haven’t told me that yet.”

HERMANN AND SAGER HOPE THEIR REsearch will continue to be funded now that they have reached the crucial stage where many of their participants are at the age where they may show symptoms of Alzheimer’s. It’s the time when the vast amount data that has been collected on the test subjects can be used to take a long look backwards and point toward causes, warning signs and cures. So far, fewer than 10 people in the study have developed Alzheimer’s.

The study has already reinforced some ideas for preventing the disease.

The latest newsletter to participants says: Keep investing in your cognitive future. Make a commitment to sustaining your brain health by staying active and engaged — physically, cognitively and socially.

“We all inherit genes that may place us at a greater or lower risk,” says Sager.

“But if you treat your brain well, you can modify that risk. For example, obesity is being connected to an increased risk of Alzheimer’s.” He advises stress reduction, exercise, avoiding smoking, sleeping eight hours a night — in general, living an active, healthy life.

One preventative measure recommended is to regularly play brain teasers and games. Some of these can be found on AARP’s website.

Insight into the diseases is badly needed. According to the Alzheimer’s Association, a new case of dementia is detectable somewhere in the world every four seconds. In the U.S., Alzheimer’s disease health care costs are $200 billion annually. In contrast, federal annual research expenditures on the disease are about $600 million — just 0.3% of what is spent caring for patients.

Those costs are certain to climb as the baby boomers age. “They could push us right over the edge,” says Sager. “The estimates are one person in eight will develop Alzheimer’s. Without a viable treatment, this could be one of the most explosive socioeconomic disasters to hit us.” n

Other aspects of Alzheimer’s research at UW-Madison When it comes to dementia research, UW-Madison is the new kid on the block.

“But it is quickly reaching national status,” says Dr. Sanjay Asthana, who heads the UW’s Alzheimer’s research program.

“Our young scientists are already leaders, and they are the future of the field.” Here’s a rundown of some of the their work:

Brain imaging in early detection of Alzheimer’s Dr. Sterling Johnson, a clinical neuropsychologist, is developing new ways to image the damage of Alzheimer’s in a living brain. Until recently, the only definitive way to diagnose Alzheimer’s was with an autopsy, which could identify abnormal growth called plaques and tangles.

“For the last eight years, we have been able to image the plaques, and now for the Sterling Johnson first time, just this year, we can image the tangles,” Johnson says. “Now that we can image both, we won’t have to wait for an autopsy.” UW-Madison is one of three sites in the country implementing this imaging technique.

4-D flow imaging Johnson is also collaborating with researchers in Medical Physics to study flow in the brain’s blood vessels. “We’ve seen that people with Alzheimer’s have lower flow going to the head, and their vessels are stiffer. This was suspected from autopsies, but no one could show it in patients until we did. We are realizing that the pulsing action of these vessels helps clear material waste out into the spinal fluid. If the vessels aren’t flexible enough, they don’t provide the pumping motion to get the garbage down the path. It stays and forms the plaques.”

New treatments for Alzheimer’s UW researchers are developing animal models to study Alzheimer’s treatments. There is no complete animal version of Alzheimer’s in the world, and that’s one of the reasons there’s been a delay in finding treatment.

However Dr. Luigi Puglielli has genetically engineered mice to express a human protein, APP, which is instrumental in developing Alzheimer’s, and the mice develop characteristics of the disease. They’re being used to better understand the molecular mechanism that triggers Alzheimer’s, so that the onset of disease can be delayed. “Within the cell, some proteins are made incorrectly. The good ones need to be marked as good to go, the others are toxic and need to be removed,” says Puglielli.

“We want to increase the natural machinery that disposes of the bad ones. Imagine that you have trash pickup once a week; as you grow older and produce more trash, you may need to remove it twice a week.”

Improved care for patients

Amy Kind

Dr. Amy Kind, associate professor in geriatrics in the UW School of Medicine, developed and piloted a Coordinated Transitional Care Program (C-TraC), to help hospitalized dementia patients return home by assigning a nurse to meet with the family and then following up with phone calls over the next several weeks. The program has reduced rehospitalization by one third and has been adopted by hospitals in Wisconsin and other states.

“We see patients and families in times of crisis,” Kind says. “And we can support them beyond their hospital stay.”

— D.T.