VU, UT researchers offer hope for Alzheimer’s grip

VUMC’s Newhouse: ‘We are poised to make some very big steps’

Friday, January 19, 2018, Vol. 42, No. 3
By Jeannie Naujeck

Few diseases are feared more than Alzheimer’s, a progressive brain disorder that steals memories, leaves no survivors and has no cure or real treatment.

But some of Tennessee’s top minds are working urgently on a way to treat the minds of the 5.2 million Americans who suffer from Alzheimer’s – including 110,000 in this state.

As more baby boomers turn 65 and enter the prime years for developing Alzheimer’s, the race for a cure is gaining new urgency among specialists in brain diseases. And through their own original research and clinical trials, scientists at Vanderbilt University Medical Center and the University of Tennessee are hoping for a breakthrough in the brain-attacking disease.

“I think we are poised to make some very big steps,” says Dr. Paul Newhouse, director of the Center for Cognitive Medicine at Vanderbilt University Medical Center.

“There are a lot of different strategies being tried now. We have great tools that we’re developing, and we’re beginning to explore multiple levels of intervention so I feel reasonably optimistic that over the next decade we will have better ways to understand the illness and recommend interventions. So, I remain optimistic.”

Vanderbilt has started Phase I testing of a new molecule, VU319, which it developed in its own labs. The molecule improves the activity of a receptor in the brain and could reduce the cognitive impairment associated with Alzheimer’s and other disorders.

Vanderbilt is also leading a national clinical trial using nicotine patches to treat memory loss.

At the University of Tennessee-Knoxville’s Pat Summitt Clinic, which just celebrated its one-year anniversary, residents of East Tennessee now have a much-needed access point for diagnosis, treatment, and the opportunity to join one of numerous clinical trials for new drugs developed by pharmaceutical companies.

And its medical director, Dr. Roberto Fernandez, is preparing to open a lab that will study the disease from the perspective of systems neuroscience.

“It’s looking at brain structure and brain function, stepping back a little bit,” Fernandez explains.

“It’s important not to forget that the brain is a very complex organ, and all these cells and molecules are working together in larger networks that communicate parts of the brain with each other.

“So, we’ve been focusing on the trees but it’s important to step back and look at the forest, too.”

Fernandez says he hopes that by looking at how Alzheimer’s spreads in the brain, and how interactions between different parts of the brain may play a role in the disease, scientists can find new and better ways of diagnosing it even before symptoms start, and then use interventions to stop it from progressing.

10 years of frustration

Such research is vitally needed. Alzheimer’s disease is primarily one of age. The vast majority of sufferers are over 65. From age 65 on, the likelihood of developing Alzheimer’s doubles every five years.

Currently, about 15 percent Americans are age 65 or older. By 2060, that number is expected to reach 24 percent.

As the population ages, neurodegenerative diseases such as Alzheimer’s are a growing public health concern. Alzheimer’s is the most common form of dementia, accounting for 60 to 80 percent of cases, and is the sixth leading cause of death in the United States.

More than 5.2 million Americans live with the disease. Without an effective treatment, that number is projected to triple in the next 30 years. It will cost an estimated $1 trillion to treat and care for those Alzheimer’s patients – not to mention the financial and emotional toll on families and caregivers.

Alzheimer’s damages and eventually destroys brain cells, leading to memory loss and changes in other brain functions. Deterioration might start slowly, with slight symptoms such as forgetting and confusion, but accelerates over time as brain cells shrink and become non-functional. In the end, it leads to complete brain failure and death.

Scientists have worked for decades to discover how the disease starts in the brain, and how to stop it, still awaiting a major breakthrough.

Much of the research has focused on two proteins – amyloid and tau –that collect in the brain of people with Alzheimer’s in the form of structures called plaques and tangles. Because plaques and tangles are hallmarks of the disease, scientists know they are very likely part of the disease process and potentially toxic to the brain.

However, clinical trials of drugs targeting those changes in the brain have not been very successful, and current approved treatments are only mildly effective at treating symptoms, not causes.

“People said 10 years ago that we would have better treatments in 10 years and it’s a little frustrating that we don’t,” Newhouse acknowledges.

“I think we have learned an enormous amount and we’ve also learned that there’s a lot we don’t know yet. The brain is the most complex structure in the known universe, so we have to look at a lot of different levels of this very complex system.”

Researchers are now taking a multi-pronged approach to deciphering Alzheimer’s causes and disease pathways, and developing new drugs for both the cause and the effects, like memory loss.

Many new clinical trials are focusing on people in the earliest stages on the theory that disease progression could be either stopped in its tracks – or at least slowed down. Genetic modification may also hold promise down the road for at least some people with genetic variants that raise their risk of Alzheimer’s.

“Alzheimer’s is like cancer. There’s not one silver bullet usually,” Newhouse adds.

“So maybe there are strategies on the molecular level, but maybe there are chemical strategies that can be used at a higher sort of nerve cell level, and then finally even more lifestyle interventions which can work at a more global level. All of these strategies have to be looked at.”

Pfizer’s exit not necessarily bad

Such research is expensive, and advocates hope that as more high-profile figures talk publicly about Alzheimer’s, the stigma will decrease, leading to more funding for a cure.

One goal of the Obama administration’s 2012 National Plan to Address Alzheimer’s Disease was to develop effective prevention and treatment methods by 2025.

But federal funding is far below what the government devotes to cancer, HIV, and other conditions that have lower mortality rates.

Last year, Congress allocated $1.4 billion for Alzheimer’s research at the National Institutes for Health. But it gave $5.4 billion to the National Cancer Institute.

Pharmaceutical companies spend about half a billion annually on research and development of new drugs, but because they are driven by profit those investments are not stable: this month, Pfizer announced it would end its research into new drugs for Alzheimer’s and Parkinson’s diseases to focus on more promising and lucrative treatments.

Newhouse doesn’t see Pfizer’s exit as a bad thing, necessarily.

“If we rely only on the private sector to do our discovery and development, we are not going to have treatments for things that are really hard to do,” he says.

“Businesses have to go where they think they can get the fastest payoff, and it may not be with the hardest disorders. In a sense, it’s an opportunity for groups like us. It’s not that Pfizer has lost interest, it’s that their own efforts are not succeeding so they’re looking for people like us to develop new molecules that they can partner with.

“A company can do two things to develop a medication: they can either do all the work themselves and develop it in their own lab ... or they can say, ‘Well, maybe we should just partner with these people that are doing the discovery in a different way.’ So, it sometimes might be better for a company to do that and that may be their strategy,” Newhouse says.

The research that led to the development of the VU319 molecule at Vanderbilt was funded in part by philanthropic private foundations, as well as the Alzheimer’s Association and a grant from the National Institutes of Health.

In November 2017, Microsoft co-founder Bill Gates pledged to invest $100 million in Alzheimer’s research and revealed that members of his own family have suffered from it. The money will go to the Dementia Discovery Fund, a private-public research partnership that will fund new approaches to the disease such as studying the brain cell’s immune system.

VU’s ‘mini drug company’

VU319 is a good example of something that was “hard to do.”

Scientists at the Vanderbilt Center for Neuroscience Drug Discovery worked on it for more than a decade. The molecule works by “tuning up” activity of an important receptor in the brain without some of the negative effects of other treatments.

If the drug succeeds, it will have big implications for the university, which is already recruiting some of the top scientists in the field.

With VU319, Vanderbilt is thought to be the first university in the country to discover a new brain drug, move it through the Food and Drug Administration’s Investigational New Drug process, and do early-stage testing on humans – all within its own walls and without a pharmaceutical company partner.

“We are very excited to be a pioneer in that regard and we are essentially like a mini drug company, developing our own molecules, so we are quite excited about that,” explains Newhouse, who designed and is leading the study on the new molecule.

“Hopefully, it will set a precedent for Vanderbilt, that we are one of the best places to do this kind of work.”

VU319 is currently in a Phase 1 trial to assess its safety in humans. The next phase will test its effectiveness in improving cognitive function and reducing memory impairment in patients with Alzheimer’s.

At the same time, Vanderbilt is also hosting a national clinical trial, Memory Improvement with Nicotine Dosing (MIND) that will test the effect of wearing a nicotine patch on memory and function in adults diagnosed with mild cognitive impairment.

Vanderbilt’s pilot study showed enough promise that the Food and Drug Administration and National Institutes of Health have approved a large, national multi-center trial. Some 30 sites around the country are participating in the trial.

Though it is usually associated with negative effects, the human brain actually has specific receptors for nicotine, and when it is separated from tobacco it has a number of important biological effects.

Newhouse describes the two trials as two ends of a spectrum.

“We have a new molecule on one end, and on the other end we are taking an old molecule that has been around for 100 years,” he says.

“We want to stimulate similar brain systems but in a slightly different way. We think that it could potentially be a very inexpensive repurposed therapy that could be used by millions of people if it turns out to work in the long run.”

The Center for Cognitive Medicine is running several other trials that focus on Alzheimer’s and the mild cognitive impairment that appears in earlier stages. It also studies brain function in diseases like HIV and cancer, as well as depression.

Additional research and clinical studies are being performed at the Vanderbilt Memory & Alzheimer’s Center, which works to identify risk factors such as vascular health and early diagnosis, and develop new treatments and preventative measures for memory loss.

Newhouse notes that the prevalence of Alzheimer’s disease is a consequence of modern medicine’s success at extending lifespan.

“We are developing aging societies around the world,” he points out.

“People are living longer and they are living healthier, but actually we run the risk of having more Alzheimer’s disease and more dementia, than we had before, because people are surviving into the ages when they develop those illnesses. So, we are dealing with the consequence of our success.

“And the hope is that we don’t have to cure this, we have to just prevent it and push it back until you die of something else.”

‘From bench to bedside’

In Knoxville, the Pat Summitt Clinic at University of Tennessee Medical Center just celebrated the one-year anniversary of its opening.

It was founded with support from the Pat Summitt Foundation to be a central point of access for Alzheimer’s treatment in East Tennessee and a major research institution. It has made big strides in its first year of operation, says medical director and renowned neurologist Dr. Roberto Fernandez.

The number of patients seen at the clinic has increased significantly and the center has added both administrative and clinical staff, including neurologists, neuropsychologists, social workers and a nurse coordinator who will help determine patient eligibility for a growing number of clinical trials.

The Pat Summitt Clinic is currently actively recruiting volunteers for two large multi-center trials for new drugs developed by the pharmaceutical industry. It will start several more within the coming weeks and months. The clinic is diversifying the trials it holds to offer options for patients with Alzheimer’s disease, those with other dementias, and patients at different stages of the disease – both the pre-clinical stages where symptoms are just starting to appear, and mild-to-moderate dementia.

“We are limited by what’s available but we always choose those that we believe have the best evidence to support them and hold the most promise to really be effective,” Fernandez says.

“Alzheimer’s is a very diverse condition. Not all Alzheimer’s patients are the same. That’s why I don’t say I treat diseases, I treat patients, because each individual is very different and they present very differently, and the disease progresses very differently in different individuals.”

Part of the longer-term plan is expanding basic scientific research. The clinic is partnering on projects with scientists in the University’s medical center and on the main campus to target mechanisms of the disease and discover potentially therapeutic new interventions to help patients.

“One of the advantages of being in a medical center that has strong research and a large clinic and patient population is that the clinician scientist and the basic scientist can oftentimes work together to move that process from bench to bedside much more quickly,” Fernandez explains.

He is also about to open his own lab, which will focus on the brain as a system rather than individual cells and molecules – an area called systems neuroscience.

“Alzheimer’s disease does not affect the entire brain equally, and we know that it tends to spread along networks or connections between parts of the brain, but we don’t know why,” he says.

“Looking at the brain as a whole, we want to figure out why certain parts are affected and how those parts might be influencing or spreading the disease to other regions. And in learning that we might be able to target certain mechanisms that maybe have not been looked at extensively before, and come up with new ways to treat and diagnose the disease, and make a difference.

“That’s not to say that what has been done is not critical – it is very important, but I think we need to be more comprehensive. And we hope that some of these areas of research will be fairly unique to the University of Tennessee and the Pat Summitt Clinic.

Fernandez is also interested in genetic research. Genetic mutations and the presence of certain genes such as APOE4 increase the risk of Alzheimer’s, and scientists hope to develop ways to “edit” these genes.

To meet his goals, Fernandez estimates he will need about $22 million. “We are very excited about what has been accomplished so far,” he explains.

“A year has gone by very quickly and that usually is an indication of how busy we have been and how much we have accomplished. But again, we are very excited about the future.”

Awareness: Coach and singer

Two high-profile Tennesseans made Alzheimer’s awareness part of their legacy. Lady Vols coach Pat Summitt suffered from relatively rare early-onset Alzheimer’s.

She was diagnosed at age 59 and died in June 2016 at age 64. Summitt vowed that the Alzheimer’s fight would continue in her name, and her foundation raised the initial money for the UT clinic.

Entertainer Glen Campbell was diagnosed in late 2010 and died in August 2017 at age 81. He consented to have his struggle with the disease filmed, even as the illness progressed, to educate the public. In the resulting documentary, I’ll Be Me, other celebrities including Brad Paisley, Bruce Springsteen, and Kathy Mattea shared their own families’ experiences with Alzheimer’s. His widow, Kim Campbell, has become an activist and advocate for caregivers.

Fernandez says such disclosures can have a big impact by reducing the shame associated with Alzheimer’s, and by encouraging people to get help early on, when the illness is most treatable.

“Alzheimer’s and dementia are words that carry a lot of weight, they are scary and they carry some stigma. We have to make people understand that there’s nothing wrong with acknowledging that you have a condition like this,” Fernandez says.

“When someone as well known and beloved as Coach Summitt comes out and speaks publicly about her diagnosis and the symptoms and her story, I think that generates attention and awareness, and it empowered many people to come here and get diagnosed in earlier stages of the disease when we can have the most impact,” he adds.

It also can increase public pressure to fund research done in laboratories like his own, which was built primarily by private donations.

“Increasing awareness so it leads to more funding is crucial. With the aging population there is a realization that this is already reaching epidemic proportions, but it will be even more so in the next 25 to 50 years. So, it’s very important to act now,” Fernandez says.

“Federal funding will continue to be critical and instrumental for research, but I think to really make the breakthroughs that need to be made, philanthropic support and contributions from individuals and private entities will be crucial and critical. The two go together and we need both.”