Background: Myeloperoxidase (MPO) is present in senile plaques and surround
ing reactive microglia, but not in normal brain parenchyma. MPO in plaques
is highest in APOE epsilon4 carriers, suggesting a functional interaction.
An MPO promoter polymorphism (-463G/A) linked to increased MPO expression h
as been associated with increased risk of AD. Methods: To further define th
e possible interaction of MPO and APOE epsilon4, we examined 127 patients w
ith 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 epsilon4 alleles relative to men carrying neither allel
e (p < 0.001; OR, 11.4; 95% CI, 3.6 to 6.7). Male APOE <epsilon>4 carriers
lacking the MPO A allele had an OR of 3.0 (p = 0.01; 95% CI, 1.3 to 6.9), i
ndicating that MPO A enhances AD risk by 3.8-fold. Age at onset was lower i
n men carrying the MPO A and APOE epsilon4 alleles (Kaplan-Meier survival a
nalysis; 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 recep
tor binding site that may contribute to these gender differences. Conclusio
ns: MPO A and APOE epsilon4 alleles interact to increase the risk of AD in
men but not in women in this Finnish cohort.