DIMENSIONS Spring 1998


by Cheryl Dawes

As Alzheimer's disease runs its relentless course, the progression of memory loss, confusion and disorientation varies. But in all individuals, the disease can be traced to molecular events in the brain that impair its function. Finding the sources of these molecular malfunctions is the goal of scientists who are searching for genes related to Alzheimer's disease (AD).

Locating a relevant gene provides the starting point for mapping the biochemical pathway or pathways that lead to a disease. In AD, that means uncovering the series of events that produces three distinctive characteristics in the brain--neurofibrillary tangles, and neuritic plaques (both of which are accumulations of abnormal proteins) and loss of neurons.

The story is complicated, however. Genes interact with each other, and with the environment, and many different biochemical pathways can lead to the same result. The challenge for AD researchers is to tease apart those interactions and isolate the individual pathways so that interventions tailored to a specific biochemical pathway can be developed.

Genes direct production of proteins, which are the workhorse molecules that make up our cells and carry out the chemical activities vital to life. In a simple model of a genetically based disease, an incorrect sequence in the building blocks that make up a gene results in flawed protein production. But Alzheimer's disease,though genetically based,is not so simple. AD has two forms--a rare, inherited form and a common form that is probably the result of complex interactions of genes and environmental factors.

Scientists, including researchers at the University of Washington Alzheimer's Disease Research Center (ADRC), have identified three genes responsible for rare, inherited forms of the disease. Another gene has been implicated as a risk factor in the common form of the disease. The discovery of each of these genes has advanced understanding of basic mechanisms of the disease and opened new avenues of investigation.

"The thing to keep in mind is that the common form of the disease, late-onset sporadic AD, accounts for 4 million Americans with Alzheimer's disease," explains George Martin, professor of pathology and director of the University of Washington ADRC. "The early familial type accounts for a minuscule proportion. The hope, which is not yet proven, is that what we learn from the early-onset familial form will be directly transferable to the common sporadic."

The first gene to be directly implicated in AD was the amyloid precursor protein (APP) gene on chromosome 21. "There are probably only 20 to 25 families in the world that have been found with a mutation in that gene," says Dr. Gerard Schellenberg, research professor of medicine and principal investigator of the ADRC Molecular Genetic Analysis Core. "Those types of mutations can result in disease that starts anywhere between 45 to 60 years of age, but it's exceedingly rare."

The next gene found to be related to Alzheimer's disease was the presenilin 1 (PS1) gene on chromosome 14. It also causes rare early-onset AD, which can occur anywhere from 30 to 60 years of age at the latest, according to Schellenberg. Research has shown that mutations in both the APP gene and in PS1 definitely lead to Alzheimer's disease.

The third AD gene, called presenilin 2 (PS2), on chromosome 1 was identified by ADRC researchers Schellenberg, Dr. Thomas Bird, Dr. Ellen Wijsman and their colleagues in 1995 (See Dimensions, Fall 1995) in families of Volga-German ancestry. Although the normal function of PS1 and PS2 proteins is probably similar because the genes are structurally similar, the results of the mutations are somewhat different, Schellenberg points out. The presence of the PS2 mutation does not mean absolutely that the disease will develop. "Within the Volga-German group, people get the disease as young as 43 and past 80. We think there are even some people who have had the mutation, lived past 80 and did not become demented," says Schellenberg.

The APP and presenilin genes are firmly linked with early-onset AD, a rare form that only occurs in a small number of families. The mutations in these genes are thought to be involved in abnormal processing of the amyloid precursor protein, creating a toxic fragment known as beta amyloid that makes up the characteristic plaques of AD.

The gene-disease connection is not so straightforward for apolipoprotein-E (APOE), the fourth AD gene to be found. APOE has been identified as a susceptibility gene for the more prevalent late onset sporadic form of the disease. There are three common variations or alleles of APOE among the general population and one of them--the E4 allele--has been implicated. "Many studies have shown that the E4 allele increases the risk for Alzheimer's disease, but it's much harder to say by how much," says Schellenberg. "Roughly 40 percent of people with Alzheimer's disease don't have the E4 allele. There are also many people who are quite old who have the E4 allele but don't have the disease."

Although APOE findings have uncovered new clues about the form of AD that affects the vast majority of people with the disease, important details of the mystery remain unsolved, including the amount of risk involved and how APOE interacts with other genetic and environmental factors. One recently published study raised new questions with results suggesting that risk associated with the E4 allele is markedly different among different ethnic groups. Although one company offers APOE as a diagnostic test for AD, the many unknowns about the gene's relationship to the disease, combined with significant ethical concerns, undermine the usefulness of such genetic testing, explains Schellenberg.

Resolution of the missing pieces of the Alzheimer's disease puzzle will entail a variety of research approaches. Schellenberg and his colleagues at the ADRC as well as other researchers around the country are continuing the search for more AD-related genes. One group has reported a linkage that may lead to identification of another gene on chromosome 12. Martin and his colleagues are using a new method called the yeast two-hybrid system to investigate genes that interact with the beta amyloid precursor protein and determine if they play a role in the disease.

"One would anticipate a number of different genes, variations of which could make small contributions to susceptibility," says Martin. "It's going to be very hard to find these things because they're small contributions, but that's precisely what you'd predict for something that takes eight or nine decades to develop. We're not looking for a sledgehammer here, we're looking for some subtlety."

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