Objective:An association between a silent polymorphism (C/T) in exon 3 of the low density lipoprotein receptor-related protein 1 (LRP1) gene and late onset Alzheimer’s disease (AD) has been reported, although with conflicting results. In the present study we tested for association between this polymorphism and AD in a sample of sporadic, early- (EOAD) and late-onset AD (LOAD) patients and age- and sex-matched control subjects from Southern Italy. Secondly, we explored a possible effect of geographic genetic variation on existing reported associations comparing our results with the findings from published studies on other European populations. Design:Case-control study. Materials and Methods:We examined this polymorphism in a cohort of 166 sporadic AD patients and 225 sex- and age-matched nondemented controls from Southern Italy. All cases fulfilled the criteria of the NINCDS/ADRDA for probable AD. The statistical analysis was performed with Pearson C2 test, Mann-Whitney test, and Cochran-Mantel-Haenszel test. The Cochran-Armitage trend test was carried out to evaluate the geographical trend among LRP1 allele and genotype frequencies in AD patients and controls of four European countries (Italy, Spain, France, and Northern Ireland) from published studies. The data were analyzed by SAS FREQ procedure (version 8.2). Exact tests were evaluated by Proc-StatXact (version 5.0). Results:No statistically significant differences were found in LRP1 genotype and allele frequencies between the whole AD sample and controls, nor in early- and late-onset subsets of AD patients. No statistically significant differences in frequencies between LRP1 alleles and AD among APOE allele, age, or gender strata were found. Finally, comparing our results with the findings from other European populations, the LRP1 C allele frequency showed a statistically significant decreasing trend from Northern to Southern regions of Europe, with a concomitant increase in LRP1 T allele frequency ,but in AD patients only. Finally, in AD sample, a decreasing geographical trend from North to South of Europe was found for LRP CC genotype, and an inverse trend for LRP1 CT genotype frequency. Conclusion:We didn’t find any evidence of association of the exon 3 LRP1 polymorphism with the disease. The possible explanations for these conflicting results are, at present, unclear. However, it is noteworthy that the original association was only described in family history-positive AD patients, while subsequent studies comprised mainly sporadic or unrelated AD cases, reporting often conflicting results. It is also possible that there is linkage disequilibrium with another biologically relevant locus on chromosome 12, such as the LRP1 ligand a2-macroglobulin. Furthermore, the different patterns of association between the exon 3 LRP1 polymorphism and AD might arise from the difference in genetic background among different populations or geographical variations, confirmed by the findings of the present study.
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