Memory lapses that occur with normal aging are a source of worry for many who fear Alzheimer's disease. Now a new Mayo Clinic-led study published in the July 16 issue of the New England Journal of Medicine suggests that the carriers of a common genetic risk factor for Alzheimer's disease begin to have memory declines in their mid-50s, far earlier than previously thought.

These and other findings reported by researchers and their colleagues in the Arizona Alzheimer's Consortium support the possibility that future Alzheimer's treatments may be most effective if started in middle-aged people, years before the onset of disabling memory and thinking problems or extensive brain pathology.

The study, which followed participants for up to 14 years, used sensitive memory and thinking tests to detect, track and compare cognitive performance in 815 healthy people, 21 to 97 years of age, with two copies, one copy and no copies of the APOE e4 gene, the major genetic risk factor for developing Alzheimer's disease at older ages. Each additional copy of this gene is associated with a higher risk of Alzheimer's disease and a slightly younger age at the onset of clinically significant memory and thinking problems.

Approximately one out of four people have one copy of the APOE e4 gene, which was inherited from one parent, and about 2 percent have two copies, which were inherited from both parents.

"We found that memory declines begin to differentiate groups of people at these three levels of genetic risk starting between ages 55 and 60, years earlier than previously suspected, and well before the anticipated onset of clinically significant symptoms," said Richard J. Caselli, M.D., Chair of Mayo Clinic's Neurology Department in Arizona and lead author of the research study. "While other age-sensitive cognitive skills also change, memory, specifically, appears to decline more quickly in APOE e4 gene carriers, and it is this pattern of cognitive aging that is similar to (but much milder than) what we expect to see in patients with Alzheimer's disease. This suggests that seemingly normal age-related memory loss may actually represent very early, preclinical-stage Alzheimer's disease."

The study was performed in collaboration with researchers from several other institutions in the Arizona Alzheimer's Consortium, including Arizona State University, Banner Alzheimer's Institute, Barrow Neurological Institute, Sun Health Research Institute, Translational Genomics Research Institute and the University of Arizona. It was supported by research grants from the National Institute on Aging and the state of Arizona.

Using brain-imaging techniques to study some of the same individuals in a previous study, the researchers reported brain changes in people at three levels of genetic risk, some of which appear decades before the onset of symptoms. They have suggested the importance of conducting prevention trials starting in late middle-age, and also suggested how brain-imaging techniques could be used to evaluate these treatments without having to study thousands of people or wait many years to see which people go on to develop symptoms.

"The current findings provide new information about the cognitive declines associated with normal aging and the extent to which they are accelerated by the major genetic risk factor for Alzheimer's disease," said Eric Reiman, M.D., Executive Director of the Banner Alzheimer's Institute, Director of the Arizona Alzheimer's Consortium, and one of the study authors.

"Perhaps more important, these findings add to the evidence that certain Alzheimer's treatments may be most effective if started not only before people develop symptoms, but even before they reach older ages."

"This study highlights the idea that Alzheimer's disease is a progressive disorder that likely begins well before clinical diagnosis," said Creighton Phelps, Ph.D., who directs the Alzheimer's Disease Research Center program for the National Institute on Aging. "Additional research is needed to identify those at high genetic risk and develop methods to delay disease progression."

Alzheimer's disease afflicts about 10 percent of people over age 65 and almost half over 85. With the skyrocketing number of people living to older ages, there is an urgent need to find demonstrably effective Alzheimer's prevention therapies. The researchers do not recommend using brain imaging or cognitive tests to predict a healthy person's risk for developing Alzheimer's later in life. But they are excited about the chance to use these techniques in cognitively normal carriers of the APOE e4 gene to evaluate promising Alzheimer's prevention therapies as quickly as possible.