The alpha 2-macroglobulin gene in AD - A population-based study and meta-analysis

Background: Whereas several authors recently reported a positive associatio n between the alpha 2-macroglobulin gene (A2M) and late-onset AD (LOAD), ot hers were unable to replicate these findings. Early-onset AD (EOAD) is defi ned as onset age <65 years. Virtually all patients with LOAD are >65 years of age. Objective: To evaluate the role of A2M in AD, the authors conducted a population-based study of LOAD and LOAD as well as a meta-analysis of al l studies conducted to date. Methods: Patients with LOAD (n = 100) were der ived from a population-based study in four northern provinces of the Nether lands and the area of metropolitan Rotterdam. Patients with LOAD (n = 344) were drawn from the Rotterdam Study, a population-based prospective study o n residents aged 55 years and over of a Rotterdam suburb in the Netherlands . Two polymorphisms were studied, A2M-I/D and A2M-Ile1000Val, in relation t o the APOE epsilon 4 allele (APOE*4). Results: No genotypic or allelic asso ciation was found for either polymorphism in the population-based series of patients with LOAD. In patients with EOAD without APOE*4, a significant in crease of carriers of A2M-1000Val was found. The meta-analysis of available published case-control data on these polymorphisms in white and mixed ethn ic populations yielded no significant differences between cases and control s. Pooling the Asian studies conducted to date showed a significant decreas e in the frequency of A2M-D among patients. Conclusions: These results sugg est that A2M is not genetically associated with LOAD in white patients or m ixed populations as found in the United States. In these populations A2M do es not have clinical relevance. From a scientific perspective, the findings on EOAD and Asian patients require replication and further research in the A2M region.