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15. The Genetics of Alzheimer Disease: Some Future Implications
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15 The Genetics of Alzheimer Disease Some Future Implications Robert Mullan Cook-Deegan The genetics of Alzheimer disease (AD), as well as genetics in general , will eventually lose its novelty and become a science that is taken for granted. Genetic techniques will be thought of, not as ways to look one by one for a gene that transmits diseases that are clearly passed within a family as Mendelian traits, but rather as tools for studying the inherited components of all diseases, including common ones. Part of this genetic dissection will identify genes that interact with other genes and genes that influence the action of (or are influenced by) hormones and growth factors, behavior, social factors, and environmental risks. AD genetics is a case study of genetics in this transition. It began by identifying genes inherited in families as autosomal dominant traits and has moved on to identify genetic risk factors that may interact with environmental factors to produce the same disease phenotype. Dr. Pollen recounted the search for genes associated with AD in Hannah’s Heirs (1996). I nonetheless want to review some of the history that seems particularly pertinent to trends portending the future of AD genetics, starting with scientific background and moving into policy issues. Some of the social implications associated with genetic testing have been anticipated and written about in the bioethics literature; others have received less attention. The definition of genetics has been broadened by molecular biology . Whereas genetics used to be the study of inheritance (the transmis- 270 Robert Mullan Cook-Deegan sion of measurable characters from one generation to the next), it is now the study of DNA structure. Genetics is expanding further to include the regulation of gene expression, and it will continue to grow. In the past, inheritance patterns were studied to infer the transmission of Mendel’s genetic elements; now, we often start with DNA and look for correlations with clinical phenotype, environmental risk, or behavior. What began as the study of genes inherited from our mothers and fathers now includes mutations passed as lineages within an organism (i.e., changes in cancer cells, lymphocytes, and others). And in recent years, the vacuous debate about nature versus nurture has finally begun to give way to the use of molecular genetics to understand function. We no longer assume we are measuring fixed genes in static Mother Nature; rather, we can now also use genes to help understand how a mother nurtures. Until the mid-1970s, most neurologists believed that genetics had little to do with AD. Brain’s Diseases of the Nervous System, the compendious neurology textbook, pointed to an instance of twin discordance to justify the straightforward conclusion that AD ‘‘is not inherited’’ (Walton 1977). A disorder was either genetic or not—and genetic meant simple Mendelian. Since so many common diseases have been shown to have Mendelian forms (i.e., families in which a condition is inherited as dominant, recessive, or X-linked traits), a contemporary medical text would not likely make the same mistake. Recognition that the same disease can be inherited in some cases and not in others tells us that there are multiple pathways to the clinical phenotype (disease) and genetic mutation is one of them. The Alzheimer story demonstrates clearly that genetic methods can move well beyond positional cloning of Mendelian mutations causing disease. AD was an early success of positional cloning—in fact, it was several success stories. The chromosome 21 story involved genetic linkage followed by the hunt for mutations in a candidate gene. The chromosome 14 story included genetic linkage followed by positional cloning. The chromosome 1 story was genetic linkage with almost simultaneous positional cloning, assisted by sequence similarity to the chromosome 14 gene. The Apolipoprotein E (ApoE) story is different. It started with linkage to chromosome 19 but moved quickly to genetic susceptibility and is now using genetics to guide epidemiology (for example, the recent clues that, among those with the E4 allele, head trauma is associated with AD). The interaction of the ApoE risk factor with the chromosome 12 timing factor may prove to be one of the first discoveries of two genes interacting to influence disease risk. [23.20.220.59] Project MUSE (2024-03-19 12:45 GMT) The Genetics of Alzheimer Disease 271 McKusick’s catalog of human genes began as Mendelian Inheritance in Man (1966) because it focused on the inheritance of those diseases clearly transmitted through families. It is now...