Genetic Testing and Alzheimers Disease

DNA testing can be performed to determine whether an individual has a mutation in one of the causative genes and/or whether he or she carries one or two copies of the APOEe4 susceptibility gene. Whether to test and which test to perform will depend on three conditions: family history of dementia, age of onset of disease, and clinical status of the individual. If a person has dementia, the test result could be useful in determining that the cause of the dementia is a form of AD. If a person has no symptoms of dementia, an estimate of the individual's risk could be developed, using the test. In the case of such estimates, both the actual accuracy of the test and the tested individual's understanding of its accuracy are of concern. While the consensus is that presymptomatic testing for causative mutations may be performed with appropriate counseling, debate over the safety and utility of APOE testing for individuals who do not show symptoms of Alzheimer's is ongoing.

In 2001, there was no treatment that prevented, much less cured, AD. Information regarding the risk of developing AD is useful only in life planning activities (such as purchasing or offering health insurance coverage or long-term care insurance coverage, or choosing retirement age) or in family planning. An individual's ability to cope with either an increased or a decreased risk may vary. Misuse of the information resulting in insurance or employment discrimination is possible. Absence of a causative gene mutation or of an APOEe4 susceptibility gene in either symptomatic or presymp-tomatic disease does not preclude AD as the cause of dementia or mean that the individual has no risk of developing AD in later years. see also Complex Traits; Disease, Genetics of; Gene Discovery; Genetic Testing; Inheritance Patterns; Psychiatric Disorders.



Mace, Nancy L., and Peter V. Rabins, eds. The 36-Hour Day, 3rd ed. Baltimore: The Johns Hopkins University Press, 1999.

St. George-Hyslop, Peter H. "Piecing Together Alzheimer's." Scientific American (Dec. 2000): 76-83.

Terry, Robert D., et al., eds. Alzheimer Disease, 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 1999.

Internet Resources

"Ethical, Legal, and Social Issues." Human Genome Project, U.S. Department of Energy Office of Science. < Genome/home.html>. "Progress Report on Alzheimer's Disease, 1999." National Institute on Aging. Bethesda: National Institutes of Health, 1999. <>.

Ames Test

The Ames test is a protocol for identifying mutagenic chemical and physical agents. Mutagens generate changes in DNA. Many mutagenic agents modify the chemical structure of adenine, thymine, guanine, and cytosine, the bases in DNA, changing their base-pairing properties and causing mutations to accumulate during DNA synthesis.

Ethyl methanesulfonate (EMS), for example, is a very potent mutagen. The ethyl group of EMS reacts with guanine in DNA, forming the abnormal base O6-ethylguanine. During DNA replication, DNA polymerases that catalyze the process frequently place thymine, instead of cytosine, opposite O6-ethylguanine. Following subsequent rounds of replication, the original G:C base pair can become an A:T pair. This changes the genetic information, is often harmful to cells, and can result in disease. Many mutagens cause a wide variety of cancers in humans.

During the 1960s the biologist Bruce Ames developed a test that still carries his name and that is still used as a relatively inexpensive way to assess the mutagenic potential of many chemical compounds. The procedure uses the bacteria Salmonella typhimurium. Wild-type S. typhimurium grows well on agar that contains only minimal nutrients. It can thrive on agar that contains only sugar, ammonium salts, phosphate, sulfate, and some trace metal ions. Amino acids are not needed because the bacteria have genes that encode enzymes that can make all twenty amino acids.

Ames developed strains of S. typhimurium that contain mutations in genes that the bacteria use to make the amino acid histidine. Such his- strains cannot survive unless histidine is added to their agar. Ames reasoned that mutagenic agents could cause changes in the aberrant gene that encodes the defective his- enzyme, causing it to revert back to the normal form, encoding the active protein. (The mutagen would likely also cause many other, undetected mutations.) A mutation that returns a function to a mutant is called a reverse mutation. The Ames test measures the ability of his- S. typhimurium to grow on agar that does not contain histidine. Growth indicates that a reverse mutation has reverted the his- gene back to an active form.

A typical Ames test involves exposing his- S. typhimurium to a test agent and then placing the exposed bacteria in petri dishes that contain agar with protocol laboratory procedure replication duplication of DNA

polymerases enzyme complexes that synthesize DNA or RNA from individual nucleotides catalyze aid in the reaction of



Ames II Salmonella unable to make histidine

Medium without histidine

Ames II Salmonella unable to make histidine

Bacterial Lawn Pic Ames Test Plate
Some Salmonella regain ability to make histidine

Modern robotic technology is used to perform the Ames test today, but the fundamental procedure remains the same. Each square represents a single well in a plastic growth plate. Mutated Salmonella (yellow) are recorded by computer-driven detectors. Courtesy of Xenometrix, Inc., a subsidiary of Discovery Partners International, Inc.

incubating heating to optimal temperature for growth no histidine. After incubating the dishes, the bacteria that have grown are counted. This number, which reflects the bacteria that undergo a reverse mutation from his- to his S. typhimurium, is compared to the number of bacteria that undergo reverse mutations when they are not exposed to the agent. If the agent causes too many reverse mutations above those measured as spontaneous, it is considered to be mutagenic.

The Ames test can detect mutagens that work directly to alter DNA. In humans, however, many chemicals are promutagens, agents that must be activated to become true mutagens. Activation, involving a chemical modification, often occurs in the liver as a consequence of normal liver activity on unusual substances. Bacteria such as S. typhimurium do not produce the enzymes required to activate promutagens, so promutagens would not be detected by the Ames test unless they were first activated. An important part of the Ames test also involves mixing the test compound with enzymes from rodent liver that convert promutagens into active mutagens. These potentially activated promutagens are then used in the Ames test. If the liver enzymes convert the agent to a mutagen, the Ames test will detect it, and it will be labeled as a promutagenic agent.

The Ames test is widely used by the pharmaceutical industry to test drugs prior to using them in clinical trials. When a drug is mutagenic in the Ames test, it is usually rejected for further development and will probably not be tested in animals or used therapeutically in humans. The cosmetic industry also uses the Ames test to assess the mutagenic potential of makeup


and other hygienic products. The Food and Drug Administration requires companies to perform the Ames test before marketing most drugs or cosmetics. see also Cancer; Carcinogens; Mutagen; Mutagenesis; Mutation; Nucleotide.

David A. Scicchitano


Ames, Bruce N., and Lois S. Gold. "The Causes and Prevention of Cancer: The Role of Environment." Biotherapy 11 (1998): 205-220.

Mortelmans, Kristien, and Errol Zeiger. "The Ames Salmonella Microsome Mutagenicity Assay." Mutation Research: Fundamental and Molecular Mechanisms of Mutagenesis 455 (2000): 29-60.

Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (AIS) is a disorder caused by mutation of the gene for the androgen receptor. This protein binds testosterone and regulates the expression of other genes that stimulate male sexual development. Testosterone is the principal male androgen. AIS is an X-linked recessive disorder that completely or partially prevents development of male sexual characteristics despite the presence of the Y chromosome. Thus, the phe-notype of a person with AIS, typified by female or ambiguous sexual characteristics, is at odds with the genotype, which includes the presence of both the X and Y, or male-determining, chromosomes.

The extent of the syndrome ranges from complete androgen insensi-tivity and development of normal external (but not internal) female sexual anatomy, to partial insensitivity, with altered or ambiguous male or female genitals, to mild insensitivity, with normal male genitals, enlarged breasts, and possibly impotence. Treatments depend on the extent of the syndrome, and may include hormone therapy, surgery, and psychological counseling. Gene testing and genetic counseling are available for families with affected members.

androgen testosterone or other masculinizing hormone phenotype observable characteristics of an organism genotype set of genes present

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