Distinct Genes Influence Alzheimer’s Risk at Different Ages

The genes that influence the risk of developing Alzheimer’s disease may vary over the course of an individual’s lifetime, a new study by Duke University Medical Center researchers finds. The team’s results revealed two chromosomal regions not previously known to influence Alzheimer’s disease: one linked to the disorder in families that first show symptoms early in life and another in families with very late onset of the disorder’s symptoms.

While earlier studies have identified genes that underlie early- versus late-onset Alzheimer’s disease, the new study is the first to indicate that distinct genes might also determine the very late onset of Alzheimer’s disease, in which symptoms first appear after the age of 80, said Duke Center for Human Genetics researcher William Scott, Ph.D., the study’s first author.

The team’s findings will appear in the November 2003 issue of The American Journal of Human Genetics. The research was supported by the National Institute on Aging and the Alzheimer’s Association. The study immediately follows another in which the Duke team identified a single gene that influences the age at onset of both Alzheimer’s and Parkinson’s diseases.

Alzheimer’s disease affects up to 4 million Americans and is the most common cause of dementia among people over the age of 65. However, some patients first experience at age 50 the mild forgetfulness characteristic of the disease’s earliest stages; for others, symptoms appear at age 80 or older.

Multiple genes underlie an individual’s risk for Alzheimer’s disease, explained Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics and leader of the study. Still other genes determine the age at which individuals first show signs of the disorder.

In their study, the team conducted a genomic screen of 437 families in which at least two members had Alzheimer’s disease.

The researchers then applied a novel method of analysis, called “ordered subsets linkage analysis,” that allowed them to identify genetic regions linked to Alzheimer’s disease specifically in families that differed in terms of their average age at onset — without making assumptions about how those age groups should be defined. In contrast, earlier methods have generally lumped people with Alzheimer’s disease into two predefined groups: early and late onset, Scott explained.

The analysis identified a region on chromosome 2 linked to Alzheimer’s disease in families with a minimum age at onset between 50 and 60 years, the researchers reported. The researchers also uncovered a second region, located on chromosome 15, linked to the disorder only in families with a minimum age at onset of 80 years.

A third region on chromosome 9, identified in an earlier genomic screen conducted by the Duke team, was found to influence late onset Alzheimer’s disease in families that experience symptoms between the ages of 60 and 75.

“By including age at onset in our analysis using this new method, we have identified genetic regions that may be associated with Alzheimer’s disease that we wouldn’t have found otherwise,” Scott said.

The researchers’ next step will be to apply additional genomic tools to identify candidate genes located in the newly identified chromosomal regions that might influence risk of Alzheimer’s disease.

Elizabeth Hauser, Ph.D., Donald Schmechel, M.D., Kathleen Welsh-Bohmer, Ph.D., John Gilbert, Ph.D., and Jeffery Vance, M.D., all of Duke, also contributed to the study. Additional researchers included Jonathan Haines, Ph.D., of Vanderbilt University Medical Center, Gary Small, M.D., of the University of California, Los Angeles; and Allen Roses, M.D., and Ann Saunders, Ph.D., of GlaxoSmithKline.