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

Alzheimers Dement. 2022 Nov;18(11):2042-2054. doi: 10.1002/alz.12607. Epub 2022 Feb 9.


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.

Keywords: Alzheimer's disease; C4B; PPP2CB; apolipoprotein E; human induced pluripotent stem cells; tau protein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Apolipoprotein E2 / genetics
  • Apolipoprotein E4 / genetics
  • Apolipoproteins E / genetics
  • Complement C4 / genetics
  • Genome-Wide Association Study
  • Humans
  • Protein Phosphatase 2 / genetics
  • tau Proteins / genetics


  • Apolipoprotein E2
  • Protein Phosphatase 2
  • Apolipoproteins E
  • Complement C4
  • Apolipoprotein E4
  • tau Proteins

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