The LRP-associated protein is involved in the amount of mature LRP expressed on liver and brain. LRP is the main ApoE receptor and also binds alpha2-macroglobulin (alpha2M), a protein that associates with the beta-amyloid protein (betaA). By binding to alpha2M, LRP is responsible for the clearance of secreted betaA, thus preventing fibril formation. Genetic variation at the APOE, A2M, and LRP genes has been associated with the risk of developing late-onset Alzheimer disease (LOAD). We genotyped 373 patients, 300 controls, and 100 healthy elderly controls for a common DNA-polymorphism at the LRPAP1 gene (Insertion/Deletion, intron 5). Homozygotes for the rare Insertion (I) allele were at a significantly lower frequency in patients compared with controls (P = 0.002; OR = 0.29; 95% CI = 0.13, 0.68), and in patients compared with healthy elderly controls (P = 0.0002; OR = 0.18; 95% CI = 0.07, 0.46). No patient with an age at the onset below 75 years was II (0 of 214) compared with 8 in the group above 75 years (8 of 159) (P = 0.0044), suggesting that this genotype delays the onset of the disease. According to our data, the variation at the LRPAP1 gene is associated with the risk of developing LOAD. This is in agreement with the role of the LRPAP1 protein in the amyloidogenic pathway.