Both functional and positional candidate gene association approaches have been employed in studies of AD, with notable successes achieved by both. Early studies focusing on functional candidates (e.g., ALDH2, ADH1B) provided replicable specific gene effects on this complex behavioral phenotype. Influence of genetic polymorphism at some loci encoding acetaldehyde dehydrogenases and alcohol dehydrogenases on risk for AD in some populations is well established, and the mechanism is very clear. Alcohol is metabolized to acetaldehyde, a toxic intermediary, by alcohol dehydrogenases; acetaldehyde is metabolized primarily by acetaldehyde dehydrogenases, the most relevant of which is encoded by ALDH2. Acetaldehyde produces a “flushing reaction” characterized by a set of uncomfortable symptoms including flushing of the skin, lightheadedness, palpitations, and nausea. A variant that reduces or eliminates ALDH function (occurring mostly in Asian populations) is protective against AD (because clearance of acetaldehyde is impeded), and ADH variants that increase function (and the production of acetaldehyde) may also be protective (see, e.g., Thomasson et al. 1991; Hasin et al. 2002; Konishi et al. 2003). Work with ALDH2 provides an instructive and intuitive example of this
