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Mario Zappia, MD; Ida Manna, PhD; Paolo Serra, PhD; Rita Cittadella, PhD; Virginia Andreoli, PhD; Antonella La Russa, PhD; Fernanda Annesi, PhD; Patrizia Spadafora, PhD; Nelide Romeo, PhD; Giuseppe Nicoletti, MD; Demetrio Messina, MD; Antonio Gambardella, MD; Aldo Quattrone, MD

Arch Neurol. 2004;61:341-344.

Background  The genes encoding myeloperoxidase (MPO) and ₂-macroglobulin (A2M) are involved in molecular pathways leading to -amyloid deposition. Two polymorphic sites in these genes (MPO-G/A and A2M-Ile/Val) have been associated with Alzheimer disease (AD), but conflicting findings have been reported in populations with different ethnic backgrounds.

Objectives  To study the association of MPO-G/A and A2M-Ile/Val polymorphisms with sporadic AD and to investigate the interactions among the MPO, A2M, and apolipoprotein E (APOE) gene polymorphisms in determining the risk of the development of AD.

Design  Case-control study.

Setting  Referral center for AD in Calabria, southern Italy.

Participants  One hundred forty-eight patients with sporadic AD and 158 healthy control subjects.

Results  The MPO-G and A2M-Val alleles were found more frequently in cases than in controls, as were the MPO-G/G and A2M-Val/Val genotypes. The odds ratio (OR) for the MPO-G/G genotype was 1.78 (95% confidence interval [CI], 1.13-2.80); for the A2M-Val/Val genotype, 3.81 (95% CI, 1.66-8.75). The presence of MPO-G/G and A2M-Val/Val genotypes synergistically increased the risk of AD (OR, 25.5; 95% CI, 4.65-139.75). Stratification of cases by sex, age at onset of AD, and APOE-4 status did not show significant differences in the distribution of MPO or A2M polymorphisms.

Conclusions  The MPO and A2M polymorphisms are associated with sporadic AD in southern Italy. Moreover, a genomic interaction between these polymorphisms increases the risk of the development of AD.

From the Institute of Neurology, University Magna Græcia, Catanzaro, Italy (Drs Zappia, Gambardella, and Quattrone); and the Institute of Neurological Sciences, National Research Council, Piano Lago–Cosenza, Italy (Drs Zappia, Manna, Serra, Cittadella, Andreoli, La Russa, Annesi, Spadafora, Romeo, Nicoletti, Messina, Gambardella, and Quattrone).