Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease

The proteins cathepsin D, encoded by CTSD gene, and α₂-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of β-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C→T and A2M-Ile/Val A→G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI) = 1.01-3.72], and 2.07 (95% CI = 1.01-4.21) after adjustment for age, sex and APOE ε4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI = 1.13-6.34) [2.82 (95% CI = 1.12-7.17) after adjustment], and to 3.29 (95% CI = 1.33-8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk.