Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease

Introduction: The apolipoprotein E (APOE) ɛ2 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 ɛ2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 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 ɛ2 carriers (P = 1.1 × 10⁻⁷) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 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 × 10⁻⁴) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10⁻⁷). Discussion: PP2A may be linked to classical complement activation leading to AD-related tau pathology.