α2-Macroglobulin (α2M) as well as its receptor, the low-density lipoprotein receptor-related (LRP) and the receptor-associated protein (RAP) are involved in the clearance of cerebral Aβ. Current evidence suggests that polymorphisms in the genes of α2M, LRP and RAP may have functional effects on the proteins. Two independent association samples of 271 AD patients and 280 representative controls were investigated whether the risk for developing AD is altered in carriers of polymorphisms in the α2M-gene (Va1000Ile), in the LRP-gene (Ala216Val) and in the RAP-gene (Val311Met). Genotypes were determined by standard PCR and restriction fragment length polymorphism. The results were adjusted for age, gender and apolipoprotein E-ε4 (APOE) polymorphism. Inheritance of α2M conferred a small increased risk for sporadic AD with an estimated Mantel-Haenszel odds ratio of 1.47. There was no age- or gender-dependent increase in α2M Val1000Ile allele frequencies in AD patients compared to controls. There was no significant difference in the allele frequencies among control and AD subjects for the LRP and RAP polymorphisms. We found no evidence of an interaction between the α2M and RAP or LRP with regard to conferred risk. Our data suggest that the α2M Val1000Ile polymorphism is weakly associated with AD. Although LRP as well as RAP seem to play an essential role in the metabolism of α2M and APOE, there is no increase in the genetic risk for AD in patients carrying the investigated polymorphisms.
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