For people free of dementia, abnormal deposits of a protein associated with Alzheimer's disease are associated with increased risk of developing the symptoms of the progressive brain disorder, according to two studies from researchers at Washington University in St. Louis. The studies, primarily funded by the National Institute on Aging (NIA), part of the National Institutes of Health, linked higher amounts of the protein deposits in dementia-free people with greater risk for developing the disease, and with loss of brain volume and subtle declines in cognitive abilities.

The two studies are reported in the Dec. 14, 2009, online issue of Archives of Neurology. The scientists used brain scans and other tests to explore the relationship between levels of beta-amyloid, a sticky protein that forms the hallmark plaques of Alzheimer's disease, and dementia risk in cognitively normal people. John C. Morris, M.D., who directs the NIA-supported Alzheimer's Disease Research Center at Washington University in St. Louis, and his team conducted the research. Martha Storandt, Ph.D., also of Washington University in St. Louis, directed one of the studies.

"Previous studies of brain pathology, cognitive testing, and brain imaging have for some time suggested that Alzheimer's pathology causes changes to the brain many years before memory loss, confusion, and other symptoms of the disease are apparent. But it remains difficult to accurately predict whether a cognitively normal person will — or will not — develop the disease," said NIA Director Richard J. Hodes, M.D. "These new studies suggest that beta-amyloid measured in the brains of cognitively normal individuals may be a preclinical sign of disease."

Morris' team used a variety of measures to look for changes in the brain in the two studies, including positron emission tomography (PET) imaging using a radioactive form of Pittsburgh Compound B (PiB), an agent specially developed to detect levels of beta-amyloid protein in the living brain; magnetic resonance imaging (MRI) to measure brain volume; and standardized clinical tests of memory and thinking abilities to determine cognitive health. Previously, the link between beta-amyloid load and Alzheimer's disease could only be confirmed at autopsy.

The studies indicated that beta-amyloid might be present in the brain even in symptom-free people:

• Between 2004 and 2008, researchers used PiB scans to track 159 volunteers ages 51 to 88, who started the study with no signs of cognitive impairment, to see if there was a correlation between beta-amyloid levels and cognitive health. Over time, 23 participants developed mild impairments, and nine were eventually diagnosed with clinical Alzheimer's disease. Compared with participants who remained cognitively normal, the nine who were eventually diagnosed clinically with Alzheimer's disease had high levels of PiB binding in the brain and experienced cognitive decline as well as volume loss in the parahippocampal gyrus, a part of the brain that controls memory. However, not every person who had beta-amyloid deposition in the brain developed cognitive impairment. Beta-amyloid deposition may be a risk factor for developing Alzheimer's disease but its presence does not constitute a diagnostic finding.
• In 135 cognitively normal older adults aged 65 to 88, the level of beta-amyloid as measured by PiB binding correlated with atrophy, or shrinkage, in many parts of the brain and to declines on memory and thinking tests over many years.

"More study is needed in larger groups for longer periods, but these studies confirm the value of detecting and measuring amyloid load in the brains of living people as soon as possible," said Morris. "These imaging tools are an important part of ongoing effort to create a profile of Alzheimer's in its earliest stages, even before symptoms appear, by linking imaging results with other biomarkers and clinical evaluations."

Additional funding came from the Charles and Joanne Knight Alzheimer's Research Initiative of the Washington University Alzheimer's Disease Research Center, St. Louis, and from an anonymous foundation.

The NIA leads the federal government effort conducting and supporting research on the biomedical, social and behavioral issues of older people. For more information on aging-related research and the NIA, go to www.nia.nih.gov. The NIA provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center site at www.nia.nih.gov/Alzheimers. To sign up for e-mail alerts about new findings or publications, please visit either website.