Abstract
Introduction The apolipoprotein E (APOE) e2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. Methods We conducted a genome-wide association study for AD among 2096 e2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in e2 carriers, was investigated using human isogenic APOE allele-specific induced pluripotent stem cell (iPSC)-derived neurons and astrocytes and in 224 neuropathologically examined human brains. Results PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among e2 carriers (P = 1.1 x 10(-7)) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 x 10(-27)). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 x 10(-4)) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 x 10(-7)). Discussion PP2A may be linked to classical complement activation leading to AD-related tau pathology.
