In Greek mythology the greatest gift the gods offered humans wasn’t just immortality—it was immortality combined with agelessness. Bestowing one without the other amounted to a curse. Nowadays, most of us would be content merely to age gracefully, and that means remaining as healthy as possible for as long as possible. That is also the goal of Mayo Clinic’s Study of Aging.

As the population ages, dementia and other aging related diseases are growing public health issues. Dementia’s prevalence among the elderly doubles every five years, from roughly one percent in persons age 60 to 65 years, to 45 percent in persons older than 95. Dementia is a significant cause of other illness, nursing–home placement and death. Without a cure, researchers seek early detection of a treatable first phase.

"What’s your secret?"

The Study of Aging team is determining how common cognitive problems are in a defined population of elderly people, along with the underlying factors associated with thought impairment and dementia. The long–term study also will help physicians better understand other age–related health problems such as hypertension and heart disease. Ultimately, Mayo hopes to provide scientific answers to the "what’s your secret?" question often posed to sprightly senior citizens.

"What we really want to know is, who are the people who age successfully? What are their characteristics?" asks Rosebud Roberts, M.B.C.h.B., a Mayo epidemiologist and
lead researcher on the study.

Dr. Roberts’ collaborators come from Mayo’s departments of neurology, psychiatry and primary care internal medicine. Their ultimate goal is to uncover the best possible research data, then translate it into the best possible patient care. Mayo Clinic has a strong commitment to collaboration among researchers and clinicians as well as cooperation across medical specialties, making it well suited to undertake such broad research.

"We have a multi–disciplinary team of scientists and physicians working on the mechanics of aging," says David Knopman, M.D., a neurologist who collaborates on the Study of Aging. "It’s a tremendous strength of ours. Unlike some research institutions, Mayo is fundamentally a clinical–care provider. We are in a unique position to try to apply things learned from our research."

For Dr. Roberts, the involvement of clinicians like Dr. Knopman makes research even more worthwhile. Physicians "hold us accountable to make the research meaningful clinically," she says, "so we’re not just producing data."

Access to a medical data goldmine

In a broad population–based study, Mayo has a unique advantage—a demographic and medical data gold mine. Olmsted County, where Mayo Clinic in Rochester, Minn. is located, has a medical records linkage system with complete health data for virtually every resident. Designed in 1966 by a Mayo physician, the Rochester Epidemiology Project links medical data from not only Mayo Clinic, but also almost all sources of medical care available to and used by the local population. The unique Project makes Olmsted County one of the few places in the world where the occurrence and natural history of diseases can be accurately described and analyzed in a defined population for many decades.

Researchers in the Study of Aging can easily retrieve data on every county resident in a specified population going back decades. Other research institutions "can’t get all the information for an individual because the records are scattered all over, or they can’t define a community," Dr. Roberts says. "Here, everyone had a chance of being included in that random selection."

Mild Cognitive Impairment

It’s common for older people to have difficulty recalling facts quickly or experience a reduced ability to multi–task. But some people may have symptoms of forgetfulness beyond normal aging—although not to the degree meeting diagnostic criteria for dementia. This intermediate stage is called Mild Cognitive Impairment.

Previous studies showed that people with MCI have a greater risk of progressing to dementia or Alzheimer’s disease (the most common form of dementia). For that reason, MCI seemed an ideal starting point for the Study of Aging.

But obtaining sound data on MCI turns out to be extremely challenging. MCI typically isn’t assessed in routine patient care and therefore may go undiagnosed. Indeed, the diagnosis of MCI is subtle and most accurate when made through an extensive personal evaluation. Earlier studies have recruited participants from memory clinics.

Another groundbreaking aspect of the Mayo study is that most participants were evaluated in person according to published criteria for MCI and dementia. The evaluations included comprehensive neurological and neuropsychological examinations, numerous cognitive assessments and the collection of blood and other samples. The latter have been stored and will provide data for possible biomarkers of MCI risk and progression. Mayo’s study is "population–based," meaning participants were randomly selected from the community. "This reduces selection bias," Dr. Roberts says.

Mayo’s data provide some of the first estimates in the U.S. of MCI in a random sample of elderly people. The study is following a group of 2,719 participants aged between 70 and 89 when the study began in 2004. Initially, the group was screened for a range of conditions including cognitive
impairment and classified as follows:

• 76.5% — normal
• 9.5% — amnestic MCI (MCI with memory loss)
• 10.3% — dementia
• 3.7% — non–amnestic MCI (MCI without memory loss)

Participants are re–evaluated every 12 to 15 months for the onset or progression of cognitive difficulties as well as other new or ongoing health conditions.

Ultimately, Mayo hopes to predict risk factors for cognitive impairment and dementia. Physicians could help prevent the onset of cognitive decline if conditions such as hypertension or diabetes turn out to be risk factors.

"A lot of these conditions are modifiable," Dr. Roberts says. "We hope that, if we intervene earlier, these people will not develop MCI, and people who have MCI may not go on to develop dementia."

Links with other diseases

Mayo Clinic already has uncovered some fascinating connections between MCI and other conditions. For example, study participants with a history of stroke were nearly three times likelier to have non–memory MCI. If those participants go on to develop dementia, Dr. Knopman says, Mayo will have evidence that cerebral vascular disease promotes dementia. And that would provide "much greater rationale for aggressive treatment of cerebral vascular risk factors earlier in life," he adds.

Some of the connections between MCI and other conditions weren’t immediately obvious. On the whole, people with diabetes in the study were no likelier to have MCI. However, digging more deeply, Dr. Roberts examined various subgroups and made some significant discoveries—those who take insulin (which implies more serious disease), those with complications from diabetes, and those who developed it before age 65 were all about twice as likely to have non–memory–loss MCI.

Similarly, participants with heart disease were roughly twice as likely to have non–memory loss MCI. On the other hand, memory–loss MCI was strongly associated with the presence of a gene called APOEe4. Previous research has linked that gene to Alzheimer’s.

"We are seeing a pattern here," Dr. Roberts says. "If you have an APOEe4 allele, you’re more likely to have MCI with memory impairment. But if you have the vascular diseases—like diabetes, hypertension, coronary heart disease—then you are more likely to have the non–memory type."

Gender and socio–economic factors also may play a role in MCI. Male study participants were more likely than women to have MCI—but not likelier to have dementia. Dr. Knopman suggests three possible reasons: the tests used to assess MCI are somehow biased against men (he considers that unlikely); men’s generally shorter life spans mean they die before progressing to dementia; or a biological difference makes male brains somehow more resistant to progression to dementia.

"We have no idea which one is right at this point," Dr. Knopman says.

Education also may be a factor: The more years of schooling participants had, the less likely they were to have MCI. Dr. Roberts says that might be due simply to higher incomes and healthier lifestyles among more–educated people. But a second, intriguing possibility is that people with more schooling are somehow able to compensate for cognitive impairment.

"Perhaps they are able to recruit other neurons to take over the job for those that are no longer functioning," Dr. Roberts says.

Relevance in the clinic

The study’s findings have particular relevance for primary–care physicians because it will help them to fine–tune their recommendations.

"We in primary care make huge efforts to intervene nowadays" with patients’ chronic health conditions such as diabetes, says Eric Tangalos, M.D., another collaborator on the Study of Aging. "People tend to think every diabetic who develops dementia has it because of cardiovascular disease, but the study suggests a direct correlation between MCI and diabetes. That encourages us to treat diabetes aggressively."

With its broad yet meticulous approach, Mayo is able to make major discoveries about the complex process of aging. The project has far–reaching implications; participants are constantly assured that "what we learn from you is going to help your grandchildren and your great–grandchildren," Dr. Roberts says. "It’s about what we can do to help everyone."

— Barbara Toman, December 2008