Alzheimer's from A to Z: Uncovering the disease
Editor's Note: This is the first of a two-part series on Alzheimer's research. Read "Part 2: Taking care of patients and families" here.
Part 1: Uncovering Alzheimer’s
Sandy Walker knew something was wrong with her husband back in 2006. Bob Walker, a man who prided himself on his intelligence, started forgetting things. His wife insisted he see their doctor to look into it.
“Bob loves to talk,” she says of the man she married nearly 54 years ago. “When he went in to the doctor they talked about everything under the sun. The doctor said, ‘There’s nothing wrong with him.’”
At the time, the Walkers lived in Pennsylvania, but shortly after they moved to Sun City, Ariz. There, they found a new doctor who saw that something was amiss right away. His diagnosis was Alzheimer’s disease.
“For a very long time, Bob covered it up really well,” says Walker, a retired nurse who now cares for her husband full-time. “He would be different at home than with other people. I almost thought I was crazy, because people would say ‘I don’t see anything wrong with him.’”
Over time, however, Bob’s decline became increasingly obvious. He still recognizes his wife, but he has trouble naming loved ones in a family photo. He asks the same questions over and over, but doesn’t always understand the answer. Physically, he has lost a lot of his strength and balance, relying on a walker to get around. Even so, he has fallen three times over the past two weeks.
Walker cares for her husband to the best of her ability. She lives with the knowledge that he will not get better.
“It’s one of the hardest things to watch somebody that you love and know their capabilities reduced to that of a two- or three-year-old child,” she says.
Across the U.S., more than five million men and women like Bob Walker are slowly losing their memories, their ability to communicate and their ability to do the things they once enjoyed. Alzheimer’s disease is the most common form of dementia – a set of illnesses that cause the loss of mental functions such as memory, language or problem solving.
Alzheimer’s affects one in nine people aged 65 and over, and one in three people aged 85 and up. Currently, there is no cure and the disease is always fatal. As it runs its course, it takes a huge emotional, physical and financial toll on both the patients and their loved ones.
Walker said she might not have moved away from Pennsylvania if she’d known her husband had Alzheimer’s, because change is very hard on patients. What she may not know, however, is that her new home state of Arizona is a national leader in Alzheimer’s disease research.
This is largely due to the Arizona Alzheimer’s Consortium (AAC), created in 1998 and funded by the National Institute on Aging and the Arizona Department of Health and Human Services. It involves about 150 researchers from seven principal institutions: Arizona State University, Banner Alzheimer’s Institute, Banner Sun Health Research Institute, Barrow Neurological Institute, Mayo Clinic Arizona, Translational Genomics Research Institute (TGen) and the University of Arizona.
The AAC has become a national model for statewide collaboration on Alzheimer’s research. The consortium takes a “more than the sum of its parts” approach, capitalizing on the complementary resources from the different institutions to address problems in more effective ways.
“Increasingly, researchers need to be able to reach out beyond their own laboratory, discipline and institution to address problems in a more compelling way. Here in Arizona, collaboration is in our genes, and it has given us the chance to have an extraordinary impact in the fight against Alzheimer’s disease,” says Eric Reiman, director of the AAC and executive director of Banner Alzheimer’s Institute in Phoenix.
This approach offers great promise in untangling the complications of Alzheimer’s disease. Scientific understanding of the disease has grown by leaps and bounds over the past couple of decades, but we are a long way from understanding many of its mysteries, including what exactly causes it and how we can detect its presence before irreversible damage has occurred.
“The problem with Alzheimer’s disease is that it’s hard to tell when it starts,” says Michael Sierks, a professor in the School for Engineering of Matter, Transport and Energy at ASU. “How it’s usually diagnosed is as a ‘what’s left’ disease. They rule out other things that can cause the symptoms. If everything else is eliminated then you’re left with Alzheimer’s.”
Alzheimer’s disease was first identified in 1906, when German psychiatrist Alois Alzheimer performed an autopsy on a patient with dementia. He produced the first images of the tangles and plaques in the brain that still serve as markers of Alzheimer’s today. But we cannot look at samples of brain tissue in living patients to diagnose the disease, and there are no lab tests that can detect it accurately. Instead, doctors diagnose Alzheimer’s based on symptoms reported by the patient and/or their loved ones.
This usually begins with memory loss beyond a person’s normal level of forgetfulness. Other symptoms include language and movement problems and, sometimes, psychiatric problems. Depression is common among Alzheimer’s patients, perhaps not surprisingly. Less common are symptoms like paranoia, belligerence and aggression.
Whatever symptoms a patient experiences, by the time they appear the disease is already well underway. When Walker first noticed changes in her husband’s behavior, which even his doctor couldn’t see, Alzheimer’s had already been attacking his brain for years, if not decades.
“The human brain is very plastic. You can lose some neurons and still function. You need to lose a lot of neurons before you can see that something’s really wrong with a person,” says Sierks, whose family history of Alzheimer’s and background in protein engineering led him to study early diagnostic tests. “At that stage it’s really hard to treat that person because a lot of the damage has already been done.”
For this reason, a lot of research today focuses on detecting the disease before symptoms appear. The goal is to create something as simple as a blood test that could be done during a routine doctor visit.
Plaques and tangles
The symptoms of Alzheimer’s disease are caused by the death of brain cells and brain tissue. The exact cause of this damage is unclear. However, the brains of people who die from Alzheimer’s disease are riddled with abnormal clumps of two protein fragments, called beta-amyloid and tau.
“Both proteins are normally expressed in cells and have a normal function,” explains Sierks. “In healthy cells, there’s a balance between the production and the clearance. In Alzheimer’s disease, the production is greater than the clearance. And the proteins start to gum up the clearance mechanism and make it go slower.”
In people with Alzheimer’s, beta-amyloid forms into plaques, which build up between neurons, or brain cells. Tau forms neurofibrillary tangles: twisted strands of protein found inside of neurons.
Most scientists now believe that beta-amyloid causes Alzheimer’s, and that its buildup produces a cascade of other effects that include the formation of tau tangles, which in turn kill neurons.
“What they’ve found from following people over 20-30 years is that they start getting plaques 15-20 years before they start showing significant symptoms of the disease,” says Sierks.
He says that it’s hard to treat people after they’ve been diagnosed because so much damage has already occurred. “At best you can hold the person where they are. What you’d really like to do is start therapy much earlier.”
Sierks is looking for early indicators of the disease, called biomarkers, which show up in the body before symptoms appear. He collaborates with Terrone Rosenberry and Pritam Das, research scientists at Mayo Clinic.
Before forming plaques and tangles, the proteins bind into smaller clumps called oligomers. Some scientists believe that these intermediary structures do the real damage of Alzheimer’s disease.
Oligomers are small enough to dissolve in fluid. This means we might be able to detect them outside of brain tissue, in cerebrospinal fluid or possibly even blood. For that reason, oligomers might serve as useful biomarkers of the disease. They might also serve as good targets for future treatments.
To detect the oligomers, Sierks develops antibodies that will bind with the specific protein clusters he’s looking for. He started by testing his antibodies in brain tissue, because he knew which samples came from people with Alzheimer’s and which came from people without the disease.
Exactly how does one go about getting samples of human brains? You pay a visit to the brain bank. It turns out Arizona is home to what Discover magazine called “the world’s preeminent brain bank.” The Banner Sun Health Research Institute’s Brain and Tissue Bank provides supremely high-quality tissue thanks to its autopsy team, which never allows more than three hours to pass between the donor’s death and the preservation of his or her brain. These tissue samples are invaluable to researchers who study Alzheimer’s disease and other neurological disorders.
“When somebody dies, things start changing in the brain pretty quickly, so you have to get samples and prepare and freeze them before things start changing,” says Sierks.
He and his colleagues have proved that their tests can differentiate between the brain tissue of Alzheimer’s patients and healthy subjects. But brain tissue can’t be used for diagnostic tests. So they have moved on to testing cerebro-spinal fluid (CSF), which surrounds the brain and spinal cord.
Unlike brain tissue, CSF can be collected from living patients, but it requires a spinal tap. That’s where Mayo Clinic comes in. Sierks’ colleagues have access to CSF samples collected from Alzheimer’s patients that the team can analyze. The Mayo researchers have also been studying different ways the proteins might aggregate, to see if there are other forms that could be detected.
“But we’d also like to be able to look at this in blood, which is easier to get. Things will diffuse across the blood-brain barrier, but they will be in much lower concentrations,” Sierks says. Therefore, his tests will have to be extremely sensitive. His main challenge now is getting blood samples taken 20-30 years before a person developed Alzheimer’s disease, when biomarkers may have first appeared.
While Sierks is developing antibodies that target the proteins found in Alzheimer’s patients, another ASU researcher believes we can use our own natural antibodies to detect the disease.
Phillip Stafford is an associate research professor in the Center for Innovations in Medicine in ASU’s Biodesign Institute. Stafford works in a field called immunosignaturing, which is based on the premise that all diseases create an immune response in the body. This response produces unique antibodies that are like a “signature,” signaling the presence of a disease even before symptoms appear.
“We haven’t found any diseases yet that don’t have a signature,” he says. “Cancer, infectious disease, even transplant patients all have a set of antibodies that are really consistent for that disease and very different from people with other diseases or healthy people.”
There is also an immunosignature for Alzheimer’s disease. However, the signature changes from the early to late stages of the disease.
“If you pick people that had confirmed Alzheimer’s disease and tried to use their antibodies to find people who were in the early stages, you probably wouldn’t succeed because it morphs. So we are trying to find people who have early indications – mild cognitive impairment – and have had blood taken,” Stafford says.
Unlike Sierks, who generates antibodies in the lab, Stafford detects antibodies that have already been raised against the defective Alzheimer’s proteins. He uses a diagnostic device that contains 10,000 to over 300,000 different peptides, all on a tiny wafer less than one centimeter long. Each of these peptides has the potential to bind to antibodies against almost any disease. A blood sample tested on this array will create a unique antibody binding pattern that can be used to identify the patient’s disease status.
This tiny device is currently being developed for a direct-to-consumer market so people could someday test themselves for cancer, Alzheimer’s and other chronic diseases.
Stafford presented his work at the AAC’s annual scientific meeting in early May. He was impressed by the group and the extent of research going on.
“Until I went to that event and started meeting with people, I didn’t realize how involved they are, and how much funding is going through it. Until you get to a meeting like this you really don’t get a chance to find other people working in the same area,” he says.
Immunizing against Alzheimer’s
A major problem with producing tests and preventions for Alzheimer’s is the time lapse between onset of the disease and appearance of symptoms. For example, if you want to learn whether lowering cholesterol in middle age can reduce the disease later in life, you’ll have to wait a long time to find out if it works, and you’ll have to study an awful lot of people.
Reiman and Pierre Tariot, a psychiatrist at Banner Alzheimer’s Institute, have found a way around this challenge in the new Alzheimer’s Prevention Initiative study. They are studying a large, extended family living in Colombia, many of whom carry a rare genetic mutation that will cause them to develop Alzheimer’s disease. The study will also include a smaller number of affected families in the U.S.
People carrying this mutation are destined to get Alzheimer’s disease. They will also get it earlier than normal – usually starting in their 40s. Fortunately, the mutation is extremely rare, accounting for less than one percent of all Alzheimer’s cases. Because it is so rare, it’s hard to find enough carriers to conduct a clinical study. However, the Colombian kindred is particularly large, with 5,000 living members, 1,500 of whom are estimated to carry the mutation.
The researchers will test an immunization developed by Genentech to see if it can prevent the disease if it is administered before symptoms appear. It is an amyloid antibody treatment judged to be the most promising candidate by an independent advisory committee.
“In addition to testing a promising treatment, our study is intended to help establish faster ways to test the range of promising prevention therapies so that we can find ones that work as soon as possible,” says Reiman. “It also includes a precedent-setting agreement with Genentech to release all the data and biological samples to the research community after the trial is over, so that researchers around the world might develop even faster ways to test prevention therapies.”
Francisco Lopera, of the University of Antioquia in Colombia, has helped the Arizona researchers establish a registry of family members that includes detailed cognitive assessments and genetic tests. They have also conducted brain imaging scans and biomarker tests in order to get as much information as possible about the early progress of the disease.
The scientists are hopeful that the immunization, administered early, will be successful. If it isn’t, they will discontinue the study and offer participants the chance to try other promising treatments. Either way, the information collected from the group will open up opportunities for other researchers, like Stafford and Sierks.
Unlike the Colombian study subjects, most people who get Alzheimer’s do not have a genetic mutation that causes the disease. Scientists do not know the exact cause of late-onset Alzheimer’s. However, variations on another gene, called APOE, can increase or decrease a person’s risk of getting Alzheimer’s. There are three forms of the gene:
• APOE2 (least common) reduces the risk slightly
• APOE3 (most common) does not affect risk
• APOE4 increases risk
“We all have two copies of every gene – one from Mom, one from Dad,” explains Richard Caselli, a neurologist at Mayo Clinic and associate director of the Arizona Alzheimer’s Disease Center. “About 20 to 25 percent of people have at least one copy of the APOE4 gene. About two percent of the population has a double dose.”
Having one copy of APOE4 increases the risk of Alzheimer’s slightly. Having two copies increases the risk significantly. Caselli and his colleagues screen large numbers of people for their APOE status and follow them over time. They have made some interesting discoveries.
First, people who have the APOE4 gene start to decline on memory performance earlier than people without it, and their decline accelerates faster. However, there is some good news for folks with two copies of APOE4. People in this group can slow the rate of decline by maintaining cardiovascular health through:
• aerobic fitness
• quitting smoking
• maintaining healthy cholesterol and blood pressure levels
• taking steps to avoid diabetes
The Alzheimer’s Prevention Registry, part of the API, will offer scientists even more opportunities to study people over the long term and find ways to prevent or slow the pace of Alzheimer’s disease. Any adult in the U.S. can join the registry, which provides news and information about Alzheimer’s disease as well as opportunities to participate in studies.
Tariot hopes the registry will engage more of the patient community in research efforts.
“Less than one percent of all affected people are involved in clinical trials. A lot of people never get specialty care and never have an opportunity to learn about research. That’s why our institute is designed the way it is – to provide not only excellent care to people but to give them information about research options,” he says.
Reiman hopes to enroll 250,000 people over the next three years. He is relying on experts at ASU to manage the project’s data and to provide legal and ethical guidance on issues like handling of genetic information.
“Our goal is to launch this new era of Alzheimer’s research, establish the framework to test the range of promising prevention therapies, and find ones that work without losing a generation,” says Reiman. “It is our hope and expectation that a scientific road to a world without Alzheimer’s disease would travel through Arizona.”
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