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Analyzing family histories of Alzheimer's disease reveals that the gene most often associated with the disease does not provide a complete picture of overall risk, according to new research from a large, epidemiological study of aging and dementia lead by Duke University Medical Center.

With the advent of genetic testing, researchers around the globe have focused their attention on studying the APOE gene. Since its discovery in 1993, numerous studies have shown that people with the E4 variant of this gene are at greater risk for developing Alzheimer's disease.

The new research is one of only a handful of studies to look at the role of both APOE and family history together to determine how cognition changes over time.

"We've learned that APOE genotype does not tell the whole genetic story," said Kathleen A. Welsh-Bohmer, Ph.D., the director of Duke's Bryan Alzheimer's Disease Research Center and the lead investigator of the Cache County Memory Study. "Other genes may be acting independently of APOE to influence someone's risk for developing the disease."

The study included residents of Cache County in northern Utah who agreed to participate in a large, epidemiological study designed to learn more about the aging process and cognitive decline. This location was selected because residents are known for their long life expectancy, many living past age 80.

More than 5,000 people aged 65 and over were enrolled in the study when it first began in 1995. A subset of 3,000 of these participants who provided DNA and details about their family history of disease were grouped depending on their family history of Alzheimer's disease and whether they had the E4 variant of the APOE gene.

"Over an average of seven and a half years of observation, the people who experienced the most significant cognitive decline had a family history of the disease and one or more copies of APOE E4," said Kathleen M. Hayden, Ph.D., assistant professor of geriatric psychiatry. She presented the findings today at the Alzheimer's Association's 2008 International Conference on Alzheimer's Disease.

"This decline was greater among those with both risk factors, which suggests there's another underlying genetic contribution to the risk of Alzheimer's disease," Hayden added. "For this reason, researchers should focus not only on people at risk because of the APOE gene, but also those who have a family history of Alzheimer's disease. Conversely, studying those who survive to late old age without disease is important to discover genes that may offer protection against the disease."

The analyses were adjusted to control for differences in age, sex and education.

"These data provide further evidence that we must explore other genetic avenues to learn more about who is at risk for cognitive decline and dementia," Welsh-Bohmer said.

The study was funded through grants from the National Institute on Aging. The study co-investigators include Peter P. Zandi of Johns Hopkins Bloomberg School of Public Health, Nancy A. West of the University of Colorado, JoAnn T. Tschanz, Maria C. Norton and Chris Corcoran of Utah State University, and John C. S. Breitner of VA Puget Sound Health Care System and University of Washington.