Association of PPP2R1A with Alzheimer's disease and specific cognitive domains

Neurobiol Aging. 2019 Sep;81:234-243. doi: 10.1016/j.neurobiolaging.2019.06.008. Epub 2019 Jul 2.

Abstract

In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease (AD), a genome-wide association study was performed on a population isolate from Eastern Canada, referred to as the Québec Founder Population (QFP). In the QFP cohort, the rs10406151 C variant on chromosome 19 is associated with higher AD risk and younger age at AD onset in APOE4- individuals. After surveying the region surrounding this intergenic polymorphism for brain cis-eQTL associations in BRAINEAC, we identified PPP2R1A as the most likely target gene modulated by the rs10406151 C variant. PPP2R1A mRNA and protein levels are elevated in multiple regions from QFP autopsy-confirmed AD brains when compared with age-matched controls. Using an independent cohort of cognitively normal individuals with a parental history of AD, we found that the rs10406151 C variant is significantly associated with lower visuospatial and constructional performances. The association of the rs10406151 C variant with AD risk appears to involve brain PPP2R1A gene expression alterations. However, the exact pathological pathway by which this variant modulates AD remains elusive.

Keywords: APOE4; Alzheimer's disease; Genome-wide association study; PPP2R1A; Quebec Founder Population; Visuospatial performance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / psychology*
  • Apolipoprotein E4 / genetics
  • Brain / metabolism
  • Chromosomes, Human, Pair 19
  • Cognition*
  • Female
  • Gene Expression
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Protein Phosphatase 2 / genetics*
  • Protein Phosphatase 2 / metabolism
  • Psychomotor Performance
  • Space Perception / physiology
  • Visual Perception / physiology

Substances

  • Apolipoprotein E4
  • PPP2R1A protein, human
  • Protein Phosphatase 2