Advancing the Science

Mayo Clinic Medical Science Blog

Share this:
August 24th, 2017

UNTANGLING ALZHEIMER’S–Mayo Clinic’s approach

By Megan Forliti

Families living with Alzheimer's disease woke to devastating newspaper headlines recently: Another highly touted drug failed in clinical trials.

Drugmaker Eli Lilly's EXPEDITION3 trial tested an antibody, a molecule used by the immune system to fight off disease, called solanezumab.

This experimental drug sought to remove harmful proteins in the brain that become building blocks for amyloid, a molecular hallmark of Alzheimer's disease. Like a garden mildew that deprives a leaf of key nutrients, amyloid proteins form into sticky clumps of plaque that kill brain cells, preventing the formation of new memories.

Not faulting the drugmaker for its efforts, media reports of the trial results nevertheless expressed varying degrees of desperation, revealing the high stakes nature of finding a true cure for Alzheimer's disease. Without an effective intervention, the number of Americans age 65 and older living with Alzheimer's is estimated to nearly triple, from 5.2 million today to 13.8 million in 2050, according to the Alzheimer's Association. Meanwhile, U.S. health care costs related to the disease are expected to increase by 360 percent to more than $1 trillion, putting Medicare, Medicaid and the global economy in a vice grip.

Despite the setbacks and statistics, one person maintaining his optimism is Mayo neurologist Ronald C. Petersen, M.D., Ph.D. In addition to directing the Mayo Clinic Alzheimer's Disease Research Center, Dr. Petersen has been appointed to numerous national and international advisory boards charged with finding an answer to what he calls the defining disorder of our generation.

With that insider perspective, Dr. Petersen has a clear message for patients and families who read the latest Alzheimer's news with trepidation: Don't give up hope.

KNOWING MORE, TRYING MORE

Ronald C. Petersen, M.D., Ph.D., is the Chester and Debbie Cadieux Director of Mayo Clinic Alzheimer's Disease Research Center and the director of the Mayo Clinic Study of Aging. He is recognized as a Mayo Clinic Distinguished Investigator and holds the Cora Kanow Professorship in Alzheimer's Disease Research.

"We know so much more about the biology of the disease than we formerly did — that is, we know about amyloid protein, how it's deposited, where it is, and now, to a large extent, how to get rid of it," Dr. Petersen says.

He notes that several clinical trials planned or underway take different approaches to targeting the root causes of Alzheimer's disease. Like the Eli Lilly trial, some clinical trials involve antibodies that attack amyloid protein at different points in its development. Other trials investigate enzyme inhibitors that prevent the amyloid development process altogether.

While amyloid has received the most attention from biotech companies, Dr. Petersen acknowledges that the recent string of drug failures may result in more treatments that target a protein called tau. If amyloid is a garden mildew caked onto a plant's leaves, tau is an invasive weed that forms tangles in the brain and blocks necessary nutrients from getting to brain cells. The affected areas are generally critical to memory development.

Exploring new ideas is a good thing, according to Dr. Petersen. He says that the research community will benefit from diversifying its treatment strategies to address the complexity of Alzheimer's disease.

"Alzheimer's is not a single cell that has failed and could be replaced and cured with stem cells," Dr. Petersen says. "Alzheimer's is a system failure in the brain."

But there's another question, one that's vitally important for a disease that doesn't usually strike until after age 65: How can research predict if and when that system will fail?

"A big criticism is that we're starting too late in the disease process," Dr. Petersen says. In many clinical trials, patients already must have documented presence of amyloid in the brain and clinical symptoms of Alzheimer's disease to meet enrollment criteria. At that point, the damage in the brain may be irreversible, rendering promising therapies useless.

"It's as if we're lowering your cholesterol as you're having a heart attack, not 10 to 15 years earlier," Dr. Petersen says. "Because of the possibility that some of these drugs actually work but are being used too late in the disease process, the field is looking toward earlier and earlier intervention."

EXPERTISE IN DEMAND

As pressure mounts to find the optimal treatment window for Alzheimer's disease, scientists are turning to Mayo Clinic for expertise that is now in high demand: Mayo's unmatched research capabilities in prediction and prevention.

To design more effective clinical trials and recruit the right patients, scientists need risk models that predict who will develop Alzheimer's disease and at what point in their life span. These risk models require imaging and biological data on large populations of people as they age over time.

Because of a unique medical records linkage system in Olmsted County, Minnesota, Mayo Clinic can conduct this population-level research through the Mayo Clinic Study of Aging. The study recruits a random sample of local study volunteers from 30 to 90 years old to better understand amyloid, tau and other dementia-related biomarkers long before an individual becomes symptomatic.

Information from the Mayo Clinic Study of Aging that is becoming more valuable to the research community includes population data on individuals who are just barely below certain biomarker-positive thresholds — for example, patients who today would test negative for amyloid but eventually become amyloid positive in a defined time frame.

"This is where a lot of Mayo's research comes into play: Where in the life span do things start to go wrong? We can then relay this information to the therapeutic community. Given this person with this background, you need to intervene at age 50, 55 or 60."

A SILVER LINING

Coupling the progress in new therapies with growing momentum behind early intervention, Dr. Petersen sees a silver lining in the solanezumab trial. "Consider that the solanezumab trial enrolled people who had documented amyloid in the brain.

That was one of the first studies to do that," Dr. Petersen says. "Thanks to advances in biomarker development, going forward, almost all studies will ask patients, 'Do you have the target that the drug is shooting at?' If yes, then the question will become, 'When should we intervene?' Already, trials are moving earlier and earlier."

As clinical trials become more sophisticated, definitive cures for Alzheimer's disease will come into view, Dr. Petersen believes.

"For instance, if research showed antibodies really work, we'd develop a vaccine against Alzheimer's disease. That way, patients don't need invasive and expensive infusions for the rest of their life starting at age 45 or so," Dr. Petersen says. "With a vaccine, the body develops its own antibodies — just like it does with the polio vaccine."

With no shortage of imagination or perseverance, the research community will push forward, Dr. Petersen concludes. And the day will come when newspapers hail a different headline: a long-awaited turning point in the journey to end Alzheimer's.

TRANSLATIONAL SCIENCE SUPERSTARS

Left to right: Walter A. Rocca, M.D., Michelle M. Mielke, Ph.D., Clifford R. Jack, M.D., Ronald C. Petersen, M.D., Ph.D., David S. Knopman, M.D., Rosebud O. Roberts, M.B., Ch.B., Bradley F. Boeve, M.D., Val Lowe, M.D.

Ronald C. Petersen, M.D., Ph.D., is quick to point out he's no lone track star when it comes to achieving Mayo Clinic's leading reputation in Alzheimer's disease research.

If anything, Mayo's physicians and scientists who study Alzheimer's and dementia function like an all-star relay team. With each lap around the track, experts in neuropathology, basic science, genetics, neuroimaging and population science pass discoveries seamlessly to one another so each can apply the rigor of their specialty to advance potential breakthroughs across the ultimate finish line: patient application.

This is called translational science, and it makes much of Dr. Petersen's work in population science possible. For instance, studying amyloid and tau in Mayo Clinic Study of Aging participants has required significant advances in neuroimaging so researchers can see the progression of these proteins over time in living people as they age. Those advances in neuroimaging are built off the work of basic scientists who reveal the true nature of disease culprits like amyloid, tau and genetic factors.

And finally, pathologists who examine postmortem brain tissues find the initial genetic or biomarker anomalies that kick the entire team into action.

"People always talk about translational research — taking basic science findings from the laboratory and applying them in the clinic to patients," Dr. Petersen says. "This is really what Mayo is built to do."

###

You can find out about more clinical trials on Mayo's clinical trials website, including many trials focusing on Alzheimer's disease.

Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. This article was originally featured on the philanthropic site "You Are...the campaign for Mayo Clinic."

Tags: About, Alzheimer's, Alzheimer's Disease Research Center, amyloid protein, dementia, Mayo Clinic Robert and Arlene Kogod Center on Aging, Mayo Clinic Study of Aging, People, Progress Updates, research, Rochester Epidemiology Project, Ronald Petersen, tau

Comment


baileyshaw437
@baileyshaw437

Posts: 4
Joined: Aug 28, 2017
Posted by @baileyshaw437, Mon, Aug 28 12:13am

Nice Post

Please login or register to post a comment.
Contact Us · Privacy Policy