Apolipoprotein E APOE

The association of APOE with inherited susceptibility to AD was uncovered by the concurrence of three lines of investigation. Genetic linkage studies in pedigrees with predominantly late-onset, famili-ally aggregated AD provided suggestive evidence (z = +2.5) for an AD susceptibility locus on chromosome 19q12-q13 near the APOE gene (Pericak-Vance et al., 1991). Second, analysis of proteins from the CSF which were capable of binding the Ab peptide revealed that one of the proteins was apolipoprotein E (APOE) (Strittmatter et al., 1993a). Finally, APOE is a component of the senile plaque of AD.

The APOE gene in humans contains three common polymorphisms: e2 (cysteines at codon 112 and codon 158); e3 (cysteines at codon 112); and e3 (arginine at codon 112). Analysis of these polymorphisms in normal control populations and in patients with AD has shown that there is an increase in the frequency of the e4 allele in patients with AD (allele frequency in AD is approximately 40%, compared to 15% in normals) (Saunders etal., 1993), and that there is a smaller reduction in the frequency of the e2 allele (from 10% to about 2% in AD) (Corder et al., 1994). More significantly, there is a dose-dependent relationship between the number of copies of e4, and the age-of-onset of AD such that e4/e4 subjects have an earlier onset than do heterozygous e4 subjects (Corder et al., 1993). Subjects with an e2 allele, on the other hand, have a later onset (Corder et al., 1994). The association between e4 and AD has been robustly confirmed in numerous studies and in several different ethnic groups. The association is weaker with advanced age of onset, and the putative protective role of the e2 allele is less clear at younger ages of onset (where it may even be associated with a more aggressive course) (Rebeck etal., 1994; van Duijn etal., 1994). This association of APOE e4 with AD has been replicated in numerous studies and in numerous ethnic groups with the possible exception of black Americans and American Hispanics, which have generated conflicting results (Hendrie et a/., 1995; Maestre et a/., 1995).

Although the association between APOE e4 and AD is robust, it is not entirely specific. Observations in patients with head injury (Mayeux et a/., 1995; Roses and Saunders, 1995); spontaneous intrace-rebral hemorrhage (Alberts et a/., 1995), and in patients undergoing elective cardiac bypass surgery (Newman et a/., 1995), all suggest a poorer outcome for patients with the e4 allele. There is a confirmed association between the e4 allele and the Lewy body variant of AD (see above) (Olichney et a/., 1996).

The mechanism by which the e4 allele is associated with an earlier onset of AD, and by which the e2 allele is associated with a later onset is unclear. The most obvious hypothesis is that APOE might influence the production, distribution, or clearance of the Ab peptide. This hypothesis is supported by observations that the genotype at APOE modulates age-of-onset in subjects carrying the ^APP Va/7177/e mutation (but not the APP692 mutation), suggesting a direct biochemical interaction between APOE and ^APP (or its metabolic products) (St George-Hyslop et a/., 1994). Second, subjects with one or more APOE e4 alleles have a higher Ab peptide plaque burden than do subjects with no e4 alleles (Schmechel et a/., 1993). In vitro studies suggest that delipidated APOE e4 binds Ab more avidly than APOE e3 (Strittmatter et a/., 1993a; 1993b). There is also evidence that both APOE and Ab may be cleared through the lipoprotein-related (LRP) receptor and that APOE e4 and the Ab peptide may compete for clearance through the LRP receptor (Kounnas et a/., 1995). Finally, transgenic mice expressing the ^APPy717F mutation (PDAPP mice) develop profound cerebral Ab deposition when bred on an APOE+/+ background, but have very little Ab deposition on an APOE_/_ background (Bales et a/., 1997).

An alternate hypothesis concerns changes in cholesterol metabolism. Both epidemiological and direct experimental evidence in cell culture models suggests that cholesterol metabolism and APP metabolism are functionally intertwined.

Specifically, reduction in cellular cholesterol availability results in significant changes in APP trafficking and processing, with the resultant reduction in Ab formation (Runz et a/., 2002). In addition, patients who have taken statins for hypercholester-olemia appear to have a reduced incidence of Alzheimer's disease (Fassbender et a/., 2001; Jick et a/., 2000; Wolozin et a/., 2000).

Finally, there is a good correlation between the degree of clinical dementia and the decrease in synaptic density in AD (Terry et a/., 1994), and it has been suggested that APOE may be involved in synaptic plasticity during regeneration and repair, and that the e4 allele is less efficient in this role. This is in accord with clinical epidemiological data suggesting that the presence of APOE e4 is associated with a poorer outcome after a variety of unrelated central nervous system injuries including head injury, stroke, and coronary artery bypass grafting. It has therefore been suggested that the association between APOE e4 and AD may not determine whether AD occurs, but rather, the clinico-pathologic response to other causative factors by modulating a variety of effects including Ab processing and regeneration-repair etc. Indeed, these putative effects of APOE on several different mechanisms need not be mutually exclusive.

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