Implication of the APP Gene in Intellectual Abilities

J Alzheimers Dis. 2017;59(2):723-735. doi: 10.3233/JAD-170049.


Background: Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC) plays an essential role.

Objectives: To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation.

Methods: The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,165). As Alzheimer's disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls).

Results: The ARC complex revealed association with verbal and total IQ (empirical p = 0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p = 0.018), within the APP gene, was confirmed in the AD sample (p = 2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2.

Discussion: This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD.

Keywords: APP; ARC; Alzheimer’s disease; Avon Longitudinal Study of Parents and Children; dementia; intelligence; synaptic plasticity.

MeSH terms

  • Alzheimer Disease / genetics
  • Amyloid beta-Protein Precursor / genetics*
  • Child
  • Computer Simulation
  • Cytoskeletal Proteins / genetics*
  • Electrophoretic Mobility Shift Assay
  • Female
  • Genotype
  • Humans
  • Intelligence / genetics*
  • Longitudinal Studies
  • Male
  • Memory / physiology
  • Models, Genetic
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Verbal Behavior


  • Amyloid beta-Protein Precursor
  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • activity regulated cytoskeletal-associated protein