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

Abstract

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.