Genetic Factors

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Advances in genetic research are among the most exciting developments in AD research. Dr. Thomas Bird, professor of neurology, medical genetics, and psychiatry at the University of Washington School of Medicine in Seattle, spoke of the progress being made in this area, noting that “we now know that there are genetic links between the disease and each of three genetic mutations on chromosomes 1, 14, and 21.”

In his review, Dr. Bird began with a mention of the defective gene on chromosome 21, a gene found to be the cause of AD in a few families with the early-onset form of the illness. This defective gene was identified as the amyloid precursor protein (APP) gene. (APP is the protein from which beta-amyloid, the chief component of the plaques seen in the brains of AD patients, is formed.)

Dr. Bird pointed out the continuing interest by researchers in Down’s syndrome–noting that as much as 99 percent of this population over the age of 40 has AD characteristics upon brain autopsy. The lifelong production of excessive amounts of beta-amyloid from chromosome 21–the chromosome present in triplicate in Down’s syndrome cases–is most likely to be the cause of the morphological brain defects of AD. Study of the consequences of this build-up in Down’s syndrome could also provide clues for AD research.

The other two mutations are known as presenilins 1 and 2, found on chromosomes 14 and 1, respectively. One of these mutations was found in families descended from Germans who had emigrated to the Volga Valley of Russia in the 1760’s, many of whom eventually came to the United States. Dr. Bird, who is credited with research leading to the discovery of presenilin 2, spoke in eloquent detail about how the disease has gripped families in these circumstances. Many of these families have watched the majority of their relatives suffer and die from AD as early as age 40, and have discussed their own fears as the genetics of the disease have become increasingly apparent in their families.

“Together, all three of these mutations [APP and presenilins 1 and 2] account for about half of all cases of early-onset familial AD,” said Dr. Bird. Discovery of the mutated genes has important implications for the small number of early-onset families in which the disease is caused by genetic mutations. In these rare families, it is possible to test family members with no symptoms of the disease to determine whether they carry the mutated gene, thus ascertaining their risk for developing the illness. Dr. Bird discussed the testing in his work with the Volga German families citing their reluctance to be tested given the almost inevitable result if they test positive for one of the mutations. He stressed the critical importance of genetic counseling and support. Many of these people, he said, exemplified the social and ethical implications of genetic testing. Though the technical ability is available, do we always want to know? he asked. Without the ability yet to actually slow the progression or onset of AD, the debate on “to test or not to test” still cannot be avoided. People are concerned about their health insurance, life insurance policies, employee discrimination, and negative social stigma. Science wants to avoid, he added, the creation of “genetic social outcasts.”

In addition to gene mutations on specific chromosomes, researchers have found that one form of the apolipoprotein E (APOE) gene, the e4 allele, appears more often among patients with the more common, late-onset form of AD than among the general population. People who inherit either one or two copies of this allele on chromosome 19 have an increased risk of developing late-onset AD. Dr. Bird underscored that APOE e4 is a risk factor gene–indicating that its inheritance does not necessarily lead to AD; and conversely, AD patients will not necessarily possess this allele. Another APOE allele, APOE e2, Dr. Bird suggested, may actually protect some people against the disease, and has been associated with lower risk and late-onset AD.

In summary, Dr. Bird told the journalists, “having multiple risk-factor alleles may increase a person’s likelihood of developing AD.” With each new finding, researchers gain more clues about basic mechanisms in AD and move closer to understanding the disease and designing treatments that slow its progression, delay its onset, or even prevent it.

Source: Connections Magazine [Volume 8(1), Spring 1999]

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