Summary: According to a new Journal of Alzheimer’s Disease study, common genetic variants in amyloid precursor protein are associated with fluid intelligence in children.
Source: IOS Press.
Rare mutations in the amyloid precursor protein (APP) have previously been shown to be strongly associated with Alzheimer’s disease (AD). Common genetic variants in this protein may also be linked to intelligence (IQ) in children, according to recent research performed at the University of Bergen, Norway.
Results of the research were published online today in the Journal of Alzheimer’s Disease. Senior author Dr. Tetyana Zayats is a researcher at the KGJebsen Centre for Neuropsychiatric Disorders at the University of Bergen.
The study analyzed genetic markers and IQ collected from 5,165 children in the Avon Longitudinal Study of Parents and Children. The genetic findings were followed up in the genetic data from two adult datasets (1) 17,008 cases with AD and 37,154 controls, and (2) 112,151 individuals assessed for general cognitive functioning. The function of the genetic markers was analysed using reporter assays in cells.
Brain cells communicate via synapses containing hundreds of specialized proteins. Mutations in some of these proteins lead to dysfunctional synapses and brain diseases such as epilepsy, intellectual disability, autism or AD. Dr. Zayats and co-workers at the University of Bergen examined a subgroup of these proteins that have been implicated in synaptic plasticity and learning (the ARC complex). They found that a variation in DNA sequence within the gene encoding a member of this group of proteins, amyloid beta precursor protein (APP) was associated with non-verbal (fluid) intelligence in children, which reflects our capacity to reason and solve problems. In adults, this variation revealed association with AD, while the overall genetic variation within the APP gene itself appeared to be correlated with the efficiency of information processing (reaction time).
“This study has potential implications for our understanding of the normal function of these synaptic proteins as well as their involvement in disease” said Dr. Zayats.
APP encodes the amyloid-β precursor protein that forms amyloid-β-containing neuritic plaques, the accumulation of which is one of the key pathological hallmarks in AD brains. However, it is unclear how these plaques affect brain functions and whether they lead to AD.
“Our understanding of biological processes underlying synaptic functioning could be expanded by examining human genetics throughout the lifespan as genetic influences may be the driving force behind the stability of our cognitive functioning,” Dr. Zayats commented.
Genetic correlation between intelligence and AD has also been found in large-scale genome-wide analyses on general cognitive ability in adults. Several genes involved in general intelligence have previously reported to be associated with AD or related dementias. Such overlap has also been noted for the APP gene, where a coding variant was shown to be protective against both AD and cognitive decline in elderly.
“While this is only an exploratory study, in-depth functional and association follow up examinations are needed,” Dr. Zayats noted. “Examining genetic overlap between cognitive functioning and AD in children – not only adults – presents us with a new avenue to further our understanding of the role of synaptic plasticity in cognitive functioning and disease.”
This work is the result of a team effort that combined statistical genetics with experimental, cellular studies carried out by first co-authors Drs. Craig Myrum, currently at the National Institutes of Health (NIH) in Baltimore, Maryland, and Oleksii Nikolaienko.
Funding: This project was funded by Stiftelsen Kristian Gerhard Jebsen, the University of Bergen, the Western Norwegian Health Authorities (Helse Vest), the Bergen Medical Research Foundation and the European Community’s Seventh Framework Programme (FP7/2007-2013; Grant no 602805).
Source: Diana Murray – IOS Press
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Original Research: Full open access research for “Implication of the APP Gene in Intellectual Abilities” by Myrum, Craig; Nikolaienko, Oleksii; Bramham, Clive R.; Haavik, Jan; and Zayats, Tetyana in Journal of Alzheimer’s Disease. Published online July 17 2017 doi:10.3233/JAD-170049
Implication of the APP Gene in Intellectual Abilities
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.
“Implication of the APP Gene in Intellectual Abilities” by Myrum, Craig; Nikolaienko, Oleksii; Bramham, Clive R.; Haavik, Jan; and Zayats, Tetyana in Journal of Alzheimer’s Disease. Published online July 17 2017 doi:10.3233/JAD-170049