Association study and meta-analysis of low-density lipoprotein receptor related protein in Alzheimer's disease

Genome scans in sporadic Alzheimer's disease (AD) have revealed a possible susceptibility locus on chromosome 12. The low density lipoprotein receptor related protein (LRP1) gene lies within this area of linkage. Eighteen previous AD case-control studies have investigated the C766T polymorphism in LRP1 with conflicting results, including a protective effect on AD of the T allele, an increased susceptibility towards AD with both the C and T alleles, or no association at all. We have now performed a case-control study based on a large UK cohort of 477 AD patients and 466 matched controls, and have included these data, with those drawn from the 18 previous studies, into in a meta-analysis of 4668 AD patients and 4473 controls. We find no evidence for influence on the risk for AD in either our own present cohort or in the combined data set. Furthermore, we investigated whether the C766T polymorphism might modify the clinical and pathological phenotype in our cohort. We found no association with AD when the cohort was stratified into those with early (<65 years) or late (>65 years) onset, or when split into Apolipoprotein E (APOE) ɛ4 bearers and ɛ4 non-bearers. In addition, the C766T polymorphism was shown not to influence the age onset of AD. In a separate autopsy-confirmed cohort of 130 AD cases, no association with genotype or allele was observed for tissue levels of β-amyloid 40, β-amyloid 42, total β-amyloid, pathological tau proteins, microglial cells or extent of astrocytic activity. Therefore, in this present study, we find no evidence for the involvement of this polymorphism either in increasing the susceptibility to AD, or by acting as a phenotypic modifier.