tively long life spans (Perls et al., 1998). It is too early to evaluate the success or failure of these studies, but there are reasons for pessimism. First of all, life span is subject to stochastic events (Finch and Kirkwood, 1999). Cancer, for example, can result in chance “hits” at particularly vulnerable parts of the genome (e.g., tumor suppressor genes). Two individuals might have the same basic rate of somatic mutations, but one may be lucky and never sustain “hits” in a tumor suppressor gene, thus escaping premature death from a cancer. Second, there is also concern that, at least for the case of human subjects, there are likely to be a very large number of genes impacting upon late-life disorders and, hence, upon life span (Martin, 1978). A proportion of such genes may be of exceptional importance, however. One such example may be the gene coding for a gene that helps to unwind double stranded DNA; when one inherits two doses of a severe mutation in that gene, it causes the Werner syndrome (Yu et al., 1996). People with that disorder display such features as premature arteriosclerosis, a variety of cancers, cataracts, osteoporosis, type 2 diabetes, gonadal atrophy, atrophy of skin and subcutaneous tissues, and premature graying and thinning of hair (Epstein et al., 1966). Twin studies indicate that perhaps a quarter of the variance of life span in humans has a genetic basis (Herskind et al., 1996). A search for these genes by large scale genomic screening of pedigrees with members exhibiting unusual longevities may therefore reveal several important genetic loci, perhaps including the Werner locus. The ascertainment of such families will require large-scale screening of populations and documentation of birth dates.

Most cases of DAT are not associated with single autosomal dominant genes and occur well after the age of 65 years, typically after the age of 85 years, when perhaps 50 percent of the population can be affected (Katzman and Kawas, 1998). Such a high “background” of affected individuals makes the search for genetic susceptibility factors very difficult. There is also the difficulty of matching cases and controls in genetic association studies. Typically, one sees the statement, in publications, that only Caucasian subjects were studied. But what is a Caucasian? That word obscures the enormous genetic heterogeneity in the U.S. population. Thus, differences in the prevalence of a particular polymorphism may be biased by an enrichment, in either controls or in diseased subjects, of a particular ethnic subtype having a different distribution frequency of the polymorphism of interest. This leads to both false positives and false negatives. These uncertainties have led to the development of various