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

The Alzheimer’s Disease Genetics Consortium

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2042-2054
Number of pages13
JournalAlzheimer's and Dementia
Issue number11
StatePublished - Nov 2022


  • Alzheimer's disease
  • C4B
  • PPP2CB
  • apolipoprotein E
  • human induced pluripotent stem cells
  • tau protein
  • Apolipoproteins E/genetics
  • Genome-Wide Association Study
  • Humans
  • Protein Phosphatase 2/genetics
  • Apolipoprotein E4/genetics
  • tau Proteins/genetics
  • Apolipoprotein E2/genetics
  • Alzheimer Disease/pathology
  • Complement C4/genetics

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Health Policy
  • Developmental Neuroscience
  • Epidemiology


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