Genetic aspects of Alzheimer disease (Table 38-1) Of some importance has been the aforementioned series of discoveries in patients with inherited forms of Alzheimer disease, of defective genes that code for errant APPs localized to chromosome 21 near the β-amyloid gene (St. George-Hyslop et al). As mentioned, this also provided an explanation for the Alzheimer changes that characterize the brains of practically all patients with the trisomy 21 defect (Down syndrome) who survive beyond their 20th year; they overproduce amyloid as a result of the triplication of the gene. But gene defects on chromosome 21 are responsible for only a small proportion of familial cases and a minuscule percentage of disease overall. Other kindreds with familial Alzheimer disease have been linked to rare dominant mutations of the presenilin genes on chromosome 14 (presenilin 1; Sherrington et al), accounting in some series for up to 50 percent of familial cases, and on chromosome 1 (presenilin 2), which may account for many of the remaining ones (Levy-Lahad et al). These are summarized in Table 38-1. The age of onset of the disease in these familial forms, as in the Down cases, is earlier than that in sporadic forms. These cohorts of patients have provided great insight into long duration between the appearance of amyloid in the brain, approximately a decade, and the onset of clinical disease, and they suggest the potential use of imaging of chemical biomarkers for the prodromal phase of the disease (The Dominantly Inherited Alzheimer Network; DIAN, see Bateman et al).
It has been clear that an excess or aberrant amyloid alone is an incomplete explanation for the disease. Certain sequence variants in normal genes confer an increased risk of the disease. The one first discovered was Apo E, a regulator of lipid metabolism that has an affinity for Aβ in Alzheimer plaques, has been found to modify the risk of acquiring Alzheimer disease. Of the several isoforms of Apo E, the presence of E4 (and its corresponding allele e4 on chromosome 19) is associated with a tripling of the risk of developing sporadic Alzheimer disease (Roses; Strittmatter et al; Polvikoski et al). This is the same allele that contributes to an elevated low-density lipoprotein fraction in the serum. Possession of two e4 alleles virtually assures the development of disease in those who survive to their eighties. The e4 allele also modifies the age of onset of some of the familial forms of the disease. In contrast, the e2 allele is underrepresented among Alzheimer patients. For these reasons it has been proposed that Apo E, by interacting with APP or tau protein in some way, modifies the formation of plaques. Indeed, possession of the e4 allele correlates with increased deposition of Aβ in the brain (McNamara). As pointed out by Hardy, Apo E appears to act at a point in the pathogenesis that is after the various genetic mutations have influenced the cellular pathology that ostensibly causes Alzheimer disease. However, these relationships do not invariably connect an allele to the disease in a particular individual. In other words, the e4 allele does not act as a mendelian trait but as a susceptibility (risk) factor. It follows that many, if not most, individuals who develop Alzheimer disease do not have the risk allele. Moreover, many individuals with the e4 allele live into their seventies and eighties without developing Alzheimer disease. All that can be stated with certainty is that, on average, the presence of the e4 allele accelerates the appearance of Alzheimer disease by about 5 years.