Abstract
The apolipoprotein E (APOE) ɛ2allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. 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. 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 ). PP2A may be linked to classical complement activation leading to AD-related tau pathology.
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