Browsing by Author "The Alzheimer’s Disease Genetics Consortium"

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    Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease
    (Wiley, 2022) Jun, Gyungah R.; You, Yang; Zhu, Congcong; Meng, Gaoyuan; Chung, Jaeyoon; Panitch, Rebecca; Hu, Junming; Xia, Weiming; The Alzheimer’s Disease Genetics Consortium; Bennett, David A.; Foroud, Tatiana M.; Wang, Li-San; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Au, Rhoda; Lunetta, Kathryn L.; Ikezu, Tsuneya; Stein, Thor D.; Farrer, Lindsay A.; Medical and Molecular Genetics, School of Medicine
    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.