Early findings from Mayo Clinic's population-based study on dementia

Who will get dementia? Can it be cured? Can it be prevented? Early detection, intervention and prevention are the motivating forces that drive clinically focused dementia research.

Mayo Clinic's approach to these research goals is unique in that it is a population-based, prospective (vs. retrospective), longitudinal research program in which cognitively healthy elderly individuals are tracked over time to see if they continue to be cognitively healthy or transition to mild cognitive impairment (MCI) or dementia.

The behavioral tracking measures are a comprehensive set of published cognitive and neuropsychological instruments. The biological measures are continually updated as advances in imaging and pathophysiological testing become available.

The study participants are randomly selected from communities within Olmsted County, Minn. The county's medical records linkage system — through the Rochester Epidemiology Project — links medical record data from Mayo Clinic and almost all other sources of medical care available to the local population. The number of participants in the study is kept to approximately 2,000 active individuals, with new participants added as needed.

The Mayo Clinic Alzheimer's Disease Research Center (ADRC) is directed by Ronald C. Petersen, M.D., Ph.D., at Mayo Clinic in Minnesota with associate directors Neill R. Graff-Radford, M.D., and Steven G. Younkin, M.D., Ph.D., at Mayo Clinic in Florida.

The population-based research study is known as the Mayo Clinic Study of Aging (MCSA). Both the center and the study are funded by the National Institute on Aging. MCSA is also supported by the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program.

Prevalence of MCI

MCI is often considered an intermediate state between normal cognitive aging and the earliest clinical signs of dementia, particularly Alzheimer's disease (AD). It can be a challenging diagnosis to make without a careful clinical evaluation because people with MCI are generally able to carry out activities of daily living and their cognitive impairments may be subtle.

One of the first goals of Mayo's population-based dementia research was to identify the prevalence of MCI (Neurology. 2010;75[10]:889-97). MCI was diagnosed using published criteria and was further characterized as either amnestic (aMCI) or nonamnestic (naMCI). Of the population sample:

Prevalence of normal cognitive aging, MCI and dementia

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• Approximately 75 percent could be classified as having normal cognitive aging; 15 percent, MCI; and 10 percent, dementia.
• The prevalence of MCI increased with age and was greater in men and in individuals with the APOE e3e4 or e4e4 genotype. APOE e4 has been associated with an increasing risk of AD.

The study also found that aMCI was 2.3 times more common than naMCI, consistent with the prevalence of AD compared with other types of dementia found in other studies. MCI also varied with years of education, with a prevalence of 11 percent in individuals with greater than 16 years of education and rising to 30.2 percent in those with fewer than nine years of education.

In discussing the greater prevalence in men than in women, the researchers noted that further analyses showed it was not due to comorbid conditions. They speculated that men may have an earlier, but more gradual, cognitive decline than women, who may transition later and more rapidly to dementia. This possibility and other questions about the robustness of cognitive health with aging, the transition to MCI and the transition from MCI to dementia will be addressed as the study continues.

Identification through imaging

Braak stages of dementia, considered the gold standard measure of tissue destruction correlated with cognitive decline, can be identified only in postmortem microscopic examination. Advances in imaging, however, are providing new, noninvasive methods of detecting structural and neurochemical changes consistent with AD and other forms of dementia.

Led by Clifford R. Jack, M.D., researchers in the Mayo Clinic Center for Advanced Imaging Research are using state-of-the-art, high-resolution imaging technology and generating new algorithms to more precisely interpret neuroimaging on an individual basis.

Among the newest of these algorithms is the Structural Abnormality Index (STAND). Developed by Prashanthi Vemuri, Ph.D., a senior research fellow in the Center for Advanced Imaging Research, it was found to accurately predict the Braak score from the MRI scans of 101 living patients. The STAND algorithm has also been used as a framework to distinguish AD from frontotemporal dementia and dementia with Lewy bodies, for which it has 75 percent to 80 percent accuracy.

As Dr. Vemuri notes, with further study and refinements, the STAND score could be used not only for detection and differential diagnosis, but also for tracking the efficacy of future medical interventions (NeuroImage. 2008;42[2]:559-67; NeuroImage. 2011;55[2]:522-31).

Prevention: lifestyle factors

Neuropsychiatric condition
Several studies have suggested that depression, apathy and agitation may predict a transition from MCI to dementia. Yonas E. Geda, M.D., a neuropsychiatrist at Mayo Clinic in Minnesota, and his colleagues conducted a prospective study of 358 individuals who had received a diagnosis of MCI in the MCSA. The investigators found a 99 percent increased risk of dementia in MCI if the person had apathy and a 66 percent increased risk of dementia if the person showed subtle signs of depression.

Dr. Geda notes that the results highlight the importance of evaluating neuropsychiatric symptoms in patients with MCI. Future research will address the question of whether treatment for depression or apathy might delay the onset of dementia.

Diet and nutrition
Diet also may have a role in cognitive decline. Rosebud O. Roberts, M.B.Ch.B., a Mayo Clinic epidemiologist, and her colleagues investigated the association between mono- and polyunsaturated fatty acids and risk of dementia (Journal of Alzheimer's Disease. 2010;21[3]:853-65).

Drawing from the MCSA participants, the researchers asked 1,233 individuals without dementia to complete a food frequency questionnaire. They found that the rate of MCI decreased with increasing mono- and polyunsaturated fatty acid intake. For example, individuals with the highest intake level had a 58 percent lower risk of MCI than those with the lowest intake.

Dr. Roberts notes that the findings are not definitive, but they add to a growing body of evidence that diet, particularly increased amounts of fatty acids, may have a role in lowering risk of MCI.

Dr. Petersen sums up the population-based effort saying, "Our first goal, for public health purposes, is to determine the rate at which healthy individuals transition to MCI and from there to dementia. The next is to predict transition using imaging and biomarkers. One advantage of a longitudinal, population-based study is that as early findings generate more questions, they can be addressed over time within the study population."