Predicting Alzheimer's

A newly identified gene may be able to predict not only the risk of developing Alzheimer's disease but also the approximate age at which the disease will begin to manifest itself.

This new gene, TOMM40, may be able to predict when Alzheimer's disease develops within a five- to seven-year window among people over sixty.

"If borne out through additional research, a doctor could evaluate a patient based on age, especially among those over age sixty, their ApoE genotype, and their TOMM40 status to calculate an estimated disease risk and age of onset," says Allen Roses HS '72, Jefferson-Pilot Professor of neurobiology and genetics and director of Duke's recently established Deane Drug Discovery Institute.

In 1993, Roses uncovered the association of apolipoprotein E (ApoE) genotypes, particularly ApoE4, with the risk and lower age of onset for Alzheimer's disease. Since then, genome-wide screening and other new techniques have been used in an attempt to build on his findings but have met with little success. So Roses' team took a different approach.

 "Genome-wide screening detects big blocks of DNA inherited together, but it doesn't tell us all the differences within that block," Roses says. That's why his team used what's known as phylogenetic analysis to track "the evolution of the DNA and to see what changes take place on the backbone of other changes."

The phylogenetic approach allows researchers to better isolate specific genes, providing deeper analysis missing from more common human genome-wide studies.

The study found that TOMM40 linked to ApoE3 had either short or long repeated sequences, while all ApoE4-linked repeat sequences were long. A longer version of TOMM40 attached to either ApoE3 or ApoE4 was significantly associated with earlier disease onset, while the short-repeat sequences were associated with a later onset of disease.

"If someone gets ApoE4 from their mother and ApoE3 from their father, they also get TOMM40 as a linked caboose," Roses says. "If the TOMM40 is a short version of the gene attached to ApoE3, then that person has a better chance of getting Alzheimer's disease very late, after age eighty. But if it's a long TOMM40, they have a better chance of getting the disease before age eighty."

Researchers now plan to validate their findings with further testing. They are proposing a five-year study combined with a drug trial aimed at preventing or delaying the onset of Alzheimer's disease.