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4 polymorphisms interact to increase risk for AD in Finnish males
From the Sidney Kimmel Cancer Center (Dr. Reynolds), San Diego, CA; Departments of Neurology (Dr. Helisalmi, Alafuzoff, and Soininen, M. Hiltunen and M. Pirskanen) and Pathology (Dr. Alafuzoff), and the Chromosome and DNA Laboratory of the Division of Diagnostic Services (Drs. Mannermaa, Helisalmi, and Lehtovirta), the University Hospital and University of Kuopio, Finland.
Address correspondence and reprint requests to Dr. Wanda F. Reynolds, Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121; e-mail: wreynolds{at}skcc.org
BACKGROUND: Myeloperoxidase (MPO) is present in senile plaques and surrounding reactive microglia, but not in normal brain parenchyma. MPO in plaques is highest in APOE 
4 carriers, suggesting a functional interaction. An MPO promoter polymorphism (-463G/A) linked to increased MPO expression has been associated with increased risk of AD.
METHODS: To further define the possible interaction of MPO and APOE 4, we examined 127 patients with AD and 174 controls from a genetically homogeneous Finnish population.
RESULTS: A significantly higher percentage of male patients with AD carried the MPO A and APOE 4 alleles relative to men carrying neither allele (p < 0.001; OR, 11.4; 95% CI, 3.6 to 6.7). Male APOE 4 carriers lacking the MPO A allele had an OR of 3.0 (p = 0.01; 95% CI, 1.3 to 6.9), indicating that MPO A enhances AD risk by 3.8-fold. Age at onset was lower in men carrying the MPO A and APOE 4 alleles (Kaplan—Meier survival analysis; p = 0.01). Also, the MPO AA genotype was associated with selective mortality in men, but not in women. AA genotypes were absent from 159 male patients with AD and controls, representing the expected 5% to 6% in women and male controls younger than age 20. The -463A creates an estrogen receptor binding site that may contribute to these gender differences.
CONCLUSTIONS: MPO A and APOE 4 alleles interact to increase the risk of AD in men but not in women in this Finnish cohort.
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