Genetic deficiency of plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) and risk of Alzheimer's disease in Japan

High plasma levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with an increased risk for cardiovascular disease, stroke and was implicated as a risk factor for dementia in the Rotterdam study, suggesting that pharmacological inhibition of this enzyme may protect from these diseases. An Asia-specific polymorphism, 994G>T (V279F) within the PLA2G7 gene encoding Lp-PLA2 is associated with absence of plasma enzyme activity. The objective of this study was to test the hypothesis that genetic deficiency of LpPLA2 activity protects against Alzheimer's disease (AD). This was a genetic case-control study of 1,952 subjects with late-onset AD (by NINCDS-ADRDA criteria) and 2,079 independent-living non-demented controls (age > 60 years) recruited from the local community in Japan as part of the Japanese Genetic Study Consortium of AD. All subjects were Japanese. PLA2G7 994G>T (SNP RS16874954) was genotyped by Taqman. Association of the PLA2G7 null mutation with AD was tested by logistic regression under an additive genotypic model adjusted for age/age of AD onset, gender, and number of apolipoprotein E (APOE) e4 alleles. Mean (SD) age at onset of the AD subjects was 74.1 (5.0), and 71% were female. Mean age of the control subjects was 75.3 (6.1), and 58% were female. 53% of AD subjects carried the APOE e4 allele, compared to 17% of controls. The frequency of the PLA2G7 null allele was 16.1% in AD subjects and 16.2% in control subjects. Genotypes were in Hardy-Weinberg equilibrium. The PLA2G7 null polymorphism was not associated with risk of AD - OR 0.98 (95% CI 0.86-1.12, p = 0.81) per additional null allele, adjusted for age/age at onset, gender, and number of APOE e4 alleles. The null polymorphism was not significantly associated with risk of AD in APOE e4 negative subjects_OR 0.92 (CI 0.79-1.09, p = 0.33)_or in APOE e4 positive subjects_OR 1.12 (CI 0.88-1.42, p = 0.35). Genetic deficiency of Lp-PLA2 activity due to carriage of 279F allele is not associated with a reduced risk of AD in Japan.