Among carriers of the apolipoprotein E4 (APOE 4) allele, serial brain imaging studies of patients treated with donepezil showed less shrinkage of the hippocampus, a structure located at the base of the brain that is key for memory function, than for study patients who received placebo (no treatment).

APOE 4 is a molecule involved in cholesterol metabolism and is a common genetic predisposition to Alzheimer's disease. All humans have a form of APOE, but APOE 4, which is present in 25% of the population, raises the likelihood of amyloid plaques forming in the brain, an important part of the pathology of Alzheimer's.

Findings will be presented July 17 at the Alzheimer's Association International Conference on Alzheimer's Disease and Related Disorders in Madrid, Spain.

"No drug has been shown to slow brain atrophy for patients with mild cognitive impairment," says Clifford Jack Jr., MD, Mayo Clinic radiologist and lead study investigator. "Our study results seem to imply that donepezil does more than provide symptom relief -- it has an effect on a measure of brain health. Our findings also show that MRI measures can have usefulness in future studies of mild cognitive impairment."

The MRI study is an adjunct study to a previously published larger study of treatment of mild cognitive impairment patients with donepezil, Vitamin E or placebo, led by Ronald Petersen, MD, PhD, Mayo Clinic neurologist. The larger study showed that donepezil slowed the rate of cognitive decline in patients with mild cognitive impairment.

The reason why there was an effect only in APOE 4 carriers remains unclear, according to Dr. Jack. "One possibility is that APOE 4 carriers were more likely to have definite Alzheimer's disease than noncarriers in the study who appear to have symptoms of early Alzheimer's disease, yet turn out to have a different diagnosis when an autopsy is performed after death," he explains.

Brain shrinkage is an essential component of Alzheimer's disease, says Dr. Jack. "In extreme cases, the brain of an Alzheimer's patient might weigh half of what a normal person's brain does at peak health."

No specific brain volume is diagnostic of Alzheimer's disease. The key, according to Mayo Clinic's Dr. Jack, is the rate of brain shrinkage relative to the volume at which a particular person's brain started.

Testing is required to know one is an APOE 4 carrier. However, experts in Alzheimer's disease do not recommend everyone undergo testing for APOE 4.

"Being an APOE 4 carrier increases one's risk for Alzheimer's disease, but many people who are carriers live into their 90s and don't get Alzheimer's," Dr. Jack says. "Others who are not APOE 4 carriers develop Alzheimer's. An analogy can be drawn to a cholesterol test, in that a person can have high cholesterol and never develop symptoms of vascular disease. On the other hand, it is not uncommon for people with acceptable cholesterol levels to suffer heart attacks and other complications of vascular disease. So, screening for APOE 4 is not recommended as a diagnostic test to predict who will develop Alzheimer's disease in the future."

Dr. Jack says another difficulty with APOE testing is that if one tests positive for APOE 4, nothing can be done about it at present. Ongoing research is investigating potential preventive treatments for those at high risk for developing Alzheimer's disease, he says.

For those who know they are APOE 4 carriers yet have no signs of mild cognitive impairment, donepezil treatment is not recommended. "It's proven useful in mild cognitive impairment and Alzheimer's disease," says Dr. Jack. "But if one is cognitively normal and an APOE 4 carrier, there is no evidence that taking donepezil is going to prevent the development of Alzheimer's."

Though donepezil is the only drug shown to affect brain shrinkage so far, other available drugs in its class have not been similarly tested for an effect on brain volume, according to Dr. Jack.

"Though the MRI findings with donepezil were measurable, this is still a very small effect. It's not like this drug stopped the disease from progressing -- it just slightly slowed the rate," he says.

The study involved taking a series of brain MRIs in 131 patients with mild cognitive impairment, starting with a baseline measurement before Vitamin E, donepezil or placebo was administered. The researchers found a positive treatment effect in measurements of the hippocampus: for APOE 4 carriers only, the rate of hippocampal atrophy was less in those treated with donepezil compared to those treated with placebo. The rate of hippocampal shrinkage in donepezil-treated APOE 4 carrier patients was 4.5% per year, versus 6.14% shrinkage in placebo-treated patients. Rates of shrinkage for cognitively normal people in their late 70s are approximately 1.4% per year.

Vitamin E had no significant effect on atrophy for any patients. The researchers also found atrophy rates were greater in those who were diagnosed with Alzheimer's disease over the course of the study.

In addition to Mayo Clinic, the University of California at San Diego and Baylor College of Medicine also were involved in this study. This study was conducted under the auspices of the Alzheimer's Disease Cooperative Study. The larger, previously published parent study was funded by the National Institute of Aging, Pfizer, Eisai and DSM Nutritional Products. The MRI adjunct study was partially funded by the Institute for the Study of Aging.