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Alzheimer's Prevention Registry Shines Light on Earliest Signs of Disease

Dan Otter worries that he and his three children might someday develop Alzheimer's disease (AD). Both of Otter's parents suffered from AD, as did several aunts and uncles. He knows it runs in families. He wants dearly to avoid the dementia that is the heartbreaking hallmark of the disease.


When he turned 50 last year, Otter decided to do what he could to help scientists in their quest to understand AD. With advice from friends in the medical field, he signed up to participate in the Wisconsin Registry for Alzheimer's Prevention (WRAP), by far the largest and oldest population-based study of healthy people at risk for Alzheimer's disease.


Otter is one of more than 1,400 people who have volunteered to be monitored for years as Wisconsin scientists search for the earliest, pre-clinical signs of the disease.


Recruiting for WRAP has never been a problem, says study director Mark Sager, MD, director of the Wisconsin Alzheimer's Institute and professor of medicine at the University of Wisconsin School of Medicine and Public Health (SMPH).


Mark Sager"Once someone in your family has this disease, you understand how devastating it is. You want to help," Sager says.


Registry May Hold Answers to Alzheimer's Questions


WRAP was way ahead of the curve when it was created in 2000.


"All the AD research 10 years ago focused on people who already had mild cognitive impairment or worse. But that's too late, the damage is already done," says Sager. "It's only when we look at people decades before symptoms arise that we can possibly understand the actual pathways that lead to AD."


Once it eventually appears, Alzheimer's disease kills brain cells, though scientists aren't sure how. Approximately 5.3 million Americans have the disease today, according to the Alzheimer's Association. And as the Baby Boom generation reaches its 60s, AD researchers feel a growing sense of urgency. Progress has been slower than expected.


But the Alzheimer's disease research community has come to agree with Sager that at-risk asymptomatic people such as those in the Wisconsin Registry for Alzheimer's Prevention study may hold the answers to many questions surrounding the disease:

  • What role do certain genes play?
  • How important is family history?
  • What are other potential risk factors?
  • What about prevention?

The WRAP cohort consists of people ages 40 to 70 from across Wisconsin and 21 other states. Otter, who flies in from Nevada, and the others have gone through a rigorous series of cognitive tests and had magnetic resonance images (MRIs) and soon will have positron emission tomography (PET) scans of their brains.


Their blood has been drawn to determine whether they carry the APOE gene, an important pre-clinical susceptibility risk factor for some but not all people who get Alzheimer's disease, and now the newest potential indicator, a gene called TOMM40.


Findings Emerge from Registry


Over time and with many tests, the UW School of Medicine and Public Health scientists have steadily monitored their Wisconsin Registry for Alzheimer's Prevention volunteers, looking for subtle changes as participants age.


A series of important findings has begun to emerge, helping to clarify the important role family history and two forms of the newly implicated TOMM40 gene, which Duke University researchers discovered last year, may have on cognitive performance and brain activity.


In the newest study, the Wisconsin researchers found that 229 of 726 WRAP volunteers who were considered at neutral risk according to their APOE status, but who carried high-risk versions of TOMM40, did significantly worse on learning and memory tests than did study participants with the low-risk version of TOMM40.


"The lower performance in the high-risk group was similar to the kinds of memory and learning changes we see in very early Alzheimer's," Sager says. "We think TOMM40 may enhance or inhibit APOE, depending on its form."


Sterling JohnsonSager presented the yet-to-be-replicated findings at the International Conference on Alzheimer's Disease in Hawaii last July. His collaborator, Sterling Johnson, PhD, associate professor of medicine at the School of Medicine and Public Health and a researcher at the Geriatric Research Education and Clinical Center at the William S. Middleton Memorial Veterans Hospital, presented other intriguing findings.


Johnson described an MRI study designed to see how the high-risk and low-risk TOMM40 might correlate with brain changes. The images showed that, compared with volunteers with the low-risk TOMM40, those with the high-risk version had significantly lower volume of gray matter in two interconnected brain regions known to be affected by Alzheimer's disease: the posterior cingulate and the hippocampus.


"This suggests that the group with the high-risk TOMM40 may be having early signs of cognitive and brain changes related to AD," Johnson says. "This evidence in the posterior cingulate could represent a 'neural signature' for AD."


In an earlier imaging study, the investigators compared the effects of family history and APOE, the well known indicator, to see which might have a stronger influence on the brain. The MRIs showed that APOE-positive subjects with a family history of Alzheimer's disease activated less of their hippocampus during memory formation tasks, regardless of their APOE genotype.


"This told us that family history accounts for a unique influence not seen with APOE," Johnson says. "Studies around the world are confirming this evidence, strengthening the possibility that additional factors-probably other genes and lifestyle factors-may also be involved."


Clearing the Confusion About Amyloid


With the help of Bradley Christian, PhD, a School of Medicine and Public Health associate professor of medical physics based at the Waisman Center, the medical school researchers are now conducting an imaging study using PET scans to "view" any amyloid plaque deposits in the brains of Wisconsin Registry for Alzheimer's Prevention participants.


Amyloid has been seen as a key factor in the development of Alzheimer's disease. Some scientists think the sticky plaques it produces, and the tangles of a protein called tau inside neurons, contribute to the destruction of brain cells. Others believe that the plaques and tangles are markers left by nerve cells killed by some other unknown cause.


"Some PET studies have shown that people with AD have a very high burden of amyloid plaque," says PET expert Christian. "But other findings show that 20 percent to 30 percent of people who don't have AD, normal controls, had a high incidence too."


Christian hopes the new National Institutes of Health-funded study will dispel some of the confusion. He'll direct the PET imaging aspects of UW-Madison's part of the multi-site clinical trial involving only centers capable of producing the special imaging compound that binds to amyloid. Christian also partnered with Sager and Johnson in earlier amyloid studies in which Otter and other WRAP volunteers participated.


Alzheimer's is a 'Disease of a Lifetime'


The School of Medicine and Public Health research findings added to the overall excitement the Alzheimer's disease research community felt during the past summer. WRAP was even featured on network television. Cumulatively, the advances represent a major step forward in potential ways to detect AD long before symptoms appear.


But the buzz stops abruptly and becomes disappointment when attention turns to treatment. The most visible indicator of this occurred in August when Ely Lilly shut down a major clinical trial on a drug that targets amyloid.


"We know existing medications don't really work for people who have progressed to AD, and we won't know for a long time if they work on at-risk people who haven't yet gotten the disease," says Sager.


But even without the prospect of effective drugs for treatment, Sager still urges WRAP participants - indeed, all his patients at risk for Alzheimer's disease - that they should not sit by and do nothing.


"The entire field is beginning to understand that mid-life risk factors, such as untreated hypertension or hypercholesteremia, are also risk factors for Alzheimer's," he says. "People who are really concerned should make sure their cholesterol is in the normal range, that they aren't overweight, that they exercise. All the lifestyle and health factors that are preventive for heart disease also work to prevent Alzheimer's disease."

It's something positive people can do as the science gradually catches up.


"We've learned over the past 10 years that this is not just a disease of old people," says Sager. "It's a disease of a lifetime. A person can have AD for decades before the brain, probably the most resistant of all organs to disease, begins to malfunction."


And it will take time before the benefits of WRAP are clear.


"We can begin to make some inferences from what we are learning from our volunteers," says Johnson, "but we will need to follow them for many years to see if the changes actually correlate with future symptoms of AD."


It's a process that requires patience, but the researchers are hopeful.


"I've never been involved in research that has the potential to make the kind of breakthroughs I think we can make with the WRAP study," says Sager.


Otter, like the other WRAP participants, is committed to the project. He plans to come back for as many years as he's asked to.


"My desire is that my children never experience Alzheimer's disease like my generation never experienced polio," Otter says. "I hope we can see those diseases as tragedies of a past generation."


By Dian Land

This article appears in the fall 2010 issue of Quarterly.

Date Published: 11/08/2010

News tag(s):  researchalzheimer's diseasemark a sagerbrainquarterlyqarchivedfeatures

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Alzheimer's Prevention Registry Shines Light on Earliest Signs of Disease

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