VNTR-DAT1 and COMTVal158Met Genotypes Modulate Mental Flexibility and Adaptive Behavior Skills in Down Syndrome

Topic: Brain proteins, microglia and lab models

Down syndrome (DS) is an aneuploidy syndrome that is caused by trisomy for human chromosome 21 resulting in a characteristic cognitive and behavioral phenotype, which includes executive functioning and adaptive behavior difficulties possibly due to prefrontal cortex (PFC) deficits. DS also present a high risk for early onset of Alzheimer Disease-like dementia. The dopamine (DA) system plays a neuromodulatory role in the activity of the PFC. Several studies have implicated trait differences in DA signaling on executive functioning based on genetic polymorphisms in the genes encoding for the catechol-O-methyltransferase ( COMTVal158Met) and the dopamine transporter (VNTR-DAT1) . Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here explore whether these polymorphisms variants interact with the trisomic genetic background to influence gene expression, and how this in turn mediates DS phenotype variability regarding PFC cognition. We genotyped 69 young adults of both genders with DS, and found that VNTR-DAT1 was in Hardy-Weinberg equilibrium but COMTVal158Met had a reduced frequency of Met allele homozygotes. In our population, genotypes conferring higher DA availability, such as Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. Met allele carriers showed worse adaptive social skills and self-direction, and increased scores in the social subscale of the Dementia Questionnaire for People with Intellectual Disabilities than Val allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population.

Key findings

• Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population.

Why it matters

In 69 young adults with Down syndrome, certain variants of the COMT and DAT1 genes were associated with better performance on executive function tasks. This concerns genetic influences on cognition in Down syndrome, not any treatment, cure or prevention of Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3389/fnbeh.2016.00193
• PubMed: 27799900
• Original source →
• Free full text: Frontiers in Behavioral Neuroscience →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{delhoyo2016-27799900,
  author  = {Del Hoyo, L. and Xicota, L. and Langohr, K. and Sánchez-Benavides, G. and de Sola, S. and Cuenca-Royo, A. and Rodriguez, J. and Rodríguez-Morató, J. and others},
  title   = {{VNTR-DAT1 and COMTVal158Met Genotypes Modulate Mental Flexibility and Adaptive Behavior Skills in Down Syndrome}},
  journal = {Frontiers in behavioral neuroscience},
  year    = {2016},
  doi     = {10.3389/fnbeh.2016.00193},
  pmid    = {27799900},
  url     = {https://doi.org/10.3389/fnbeh.2016.00193}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Down syndrome phenotypes: the consequences of chromosomal imbalance Proceedings of the National Academy of Sciences of the United States of America · 1994-05-01 · usefulness score 52/100 · Down syndrome and Alzheimer's
• Similar deficits of central histaminergic system in patients with Down syndrome and Alzheimer disease Neuroscience letters · 1997-02-01 · usefulness score 38/100 · Down syndrome and Alzheimer's

Related studies in Down syndrome and Alzheimer's

• Age, adaptive behavior, and Alzheimer disease in Down syndrome: cross-sectional and longitudinal analyses American journal of mental retardation : AJMR · 1994-09-01 · usefulness score 37/100
• Monoacylglycerol lipase inhibitor JZL184 improves behavior and neural properties in Ts65Dn mice, a model of down syndrome PloS one · 2014-12-04 · usefulness score 42/100
• Allele varepsilon4 of apolipoprotein E gene is less frequent in Down syndrome patient of the Sicilian population and has no influence on the grade of mental retardation Neuroscience letters · 2001-06-01 · usefulness score 36/100
• Microglial activation induced by factor(s) contained in sera from Alzheimer-related ApoE genotypes Journal of neuroscience research · 1998-11-01 · usefulness score 35/100
• Adaptive downregulation of mitochondrial function in down syndrome Cell metabolism · 2013-01-01 · usefulness score 36/100
• Early behavioural and adaptive markers of dementia in adults with Down syndrome International Journal of Intellectual Disability · 2026-07-01 · usefulness score 32/100

Also tagged “down”

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• Frameshift proteins in autosomal dominant forms of Alzheimer disease and other tauopathies Neurology · 2006-01-01 · usefulness score 39/100 · Down syndrome and Alzheimer's
• Glucose, memory, and aging The American journal of clinical nutrition · 1998-04-01 · usefulness score 40/100 · Down syndrome and Alzheimer's
• Longitudinal Clinical and Cognitive Changes Along the Alzheimer Disease Continuum in Down Syndrome JAMA network open · 2022-08-01 · usefulness score 66/100 · Down syndrome and Alzheimer's

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• A review that covers this ground Progressive worsening of adaptive functions in Down syndrome may be mediated by the complexing of soluble Abeta peptides with the alpha 7 nicotinic acetylcholine receptor: therapeutic implications Clinical neuropharmacology · 2003-09-01 · usefulness score 31/100
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