-
7. The History of the Genetics of Alzheimer Disease
- Johns Hopkins University Press
- Chapter
- Additional Information
7 The History of the Genetics of Alzheimer Disease Daniel A. Pollen This chapter reviews the major advances in the genetics of Alzheimer disease (AD), together with several issues that have proved inseparable from the discovery of the genes themselves. For diseases of unknown gene product, gene discovery is often the first step in understanding disease pathogenesis. In the protracted period between gene discovery and treatment, however, the issues of predictive genetic testing create both options and dilemmas for an ever-increasing percentage of the population. Moreover, the discovery of susceptibility genes for late-onset AD has provided opportunities to determine how environmental factors modify gene products and disease progression. I begin with the history of the recognition of genetic factors in AD (Pollen 1996). Following the 1907 publication of Alois Alzheimer’s three-page report on a case of presenile dementia, Kraepelin proposed in 1910 that the presenile form of dementia be designated as ‘‘Alzheimer’s Disease.’’ By then, Alzheimer had already astutely surmised that atherosclerotic vascular abnormalities were unrelated to the senile processes observed in the brain in late life. Alzheimer accepted Kraepelin’s designation of AD with considerable caution and was never certain whether the presenile disease was simply an unusually severe and premature form of senile dementia. Indeed, he and others at the time thought that there were neuropathological 116 Daniel A. Pollen differences in the two forms—with frontal lobe pathology being more severe in senile dementia and with greater devastation of temporal and parietal lobes occurring in presenile dementias. Even the distinctions between senile dementia and normal aging were not yet clear. In 1911 Perusini could find no clear-cut distinction between senile dementia and normal aging—at least as far as the presence, though not the extent, of the senile plaques was concerned (Bick, Amaducci, and Pepeu 1987). While there is a great risk of oversimplification in summarizing the history that led to the discovery of the first known gene to cause AD, certain landmarks stand out. Between 1927 and 1934, Paul Divry in Belgium defined the ‘‘peculiar substance’’ in the cerebral plaques as ‘‘amyloid,’’ a then-obscure class of substances defined by characteristic staining reactions. Contemporaneously, in Germany in 1929, Fredric Strüwe discovered numerous senile plaques in the brains of relatively young patients dying with Down syndrome. Studies of such patients provided the first evidence of a convergent process common to victims of Down syndrome and AD. By 1932 the first reports that AD might occur on a familial basis came from Germany in independent reports by Shottky and Von Braunmühl. In the United States in 1934, Rothschild documented the higher incidence of AD in females. In England a decade later, this remarkable difference inspired Mayer-Gross’s (1944) observation that ‘‘a completely unexplained feature of Alzheimer’s disease is its prevalence in females.’’ By 1948 Jervis had discovered that some patients with Down syndrome develop a dementia in their late 30s and 40s that resembles AD. Although R. D. Newton (1948) saw a continuum between presenile dementia, senile dementia, and what he called ‘‘normal senility,’’ he nevertheless suspected that obscure genetic factors took hold at vastly distinct stages of life. In 1958 the French geneticist Jerome Lejeune discovered that Down syndrome was caused by a duplication or extra copy of chromosome 21, hence the new term ‘‘trisomy 21.’’ By 1977 Heston in the United States realized that the increased incidence of AD in persons with Down syndrome might be attributable to the extra copy of some gene on chromosome 21. EARLY-ONSET ALZHEIMER DISEASE The search for the genetic basis of the various forms of early-onset AD took on new momentum in the 1983–84 period. Jim Gusella’s 1983 [107.23.85.179] Project MUSE (2024-03-19 03:44 GMT) The History of the Genetics 117 discovery of the linkage of Huntington disease to the short arm of chromosome 4 initiated the use of ‘‘reverse genetics’’—that is, using DNA markers for linkage analysis to discover the genetic causes of diseases of unknown gene product. Indeed, only one of the AD genes has been discovered on the basis of a putative gene product. That discovery may be traced back to Glenner and Wong, who in 1984 isolated, purified, and sequenced the vascular amyloid peptide. If b-amyloid is a gene product, they suggested that perhaps the genetic defect for both AD and Down syndrome resided on chromosome 21. Within a year, Beyreuther...