Association of the C766T polymorphism of the low‐density lipoprotein receptor‐related protein gene with Alzheimer's disease

Abstract

The low-density lipoprotein receptor-related protein (LRP) is one of the most important cholesterol receptors in the brain. Gene variation of its ligand, apolipoprotein E, is a major genetic risk-factor for Alzheimer's disease (AD). The C-allele of the silent C766T polymorphism in exon 3 of the LRP gene might be associated with AD, however, results are conflicting and thus discussed controversially. Consequently, we compared the prevalence of this polymorphism in a homogenous cohort of patients with AD and control subjects. We found that carriers of a C-allele were at lower risk of AD; in agreement with this observation, AD patients who were carriers of a C-allele presented with a later age at onset of the disease than carriers of the TT genotype. These data suggest that LRP polymorphism influences the risk as well as the age at onset of AD. Our results contrast with other studies which described the C-allele to be a risk-factor for AD, but are in line with a recent publication on the effect of LRP polymorphism on longevity and on the risk for coronary artery disease. Further research on LRP polymorphisms is needed to evaluate their effects on the risk of AD, on coronary artery disease and on longevity.

Relation of Apolipoprotein(a) Size to Alzheimer’s Disease and Vascular Dementia

“…Furthermore, it has been reported that different sized apo(a) isoforms differ by their interaction with low density lipoprotein receptor-related protein/· 2 macroglobulin receptor (LRP) [21]. Since LRP has been implicated in the pathogenesis of AD [22], we postulated a possible involvement of apo(a) size polymorphism in the aetiology of degenerative dementia. Furthermore, apo(a) size could directly influence the prothrombotic properties of Lp(a) by binding to fibrin in a sizedependent manner [23].…”

APP Processing and the APP-KPI Domain Involvement in the Amyloid Cascade

“…The Abeta/chaperone complexes then bind to LRP via binding sites on ApoE or alpha(2)M. Finally, clearing Abeta from the brain into the circulation by vascular transport across the BBB is mediated mainly via LRP-1 in brain microvascular endothelium. Remarkably, LRP and its ligands, ApoE and alpha2M, are all genetically associated with AD [47][48][49] . This mechanism is age dependent, and lower clearance rates in older animals correlate with decreased vascular levels of LRP [50] .…”

Association of polymorphisms in the LRP1 and A2M genes with Alzheimer’s disease in the Northern Chinese Han population

“…But the results were conflicting; some studies showed that the C allele might increase the risk of SAD, while other studies found that the C allele was protective. [5][6][7] A2M is a protease inhibitor which is upregulated in the brains of patients with AD and increases degradation of the Ab peptide and inhibits b-sheet and fibril formation. 8 An association between the A2M I1000V polymorphism in exon 24 and increased risk of AD has been reported, [9][10][11] but other studies have failed to confirm these results.…”