Abstract
The potential of putative cognitive-enhancing compounds to improve mental processing both in healthy and vulnerable populations is an area of growing interest to scientific and clinical communities. The possible influence of individual genetic differences on efficacy of these compounds has yet to be considered. We sought to investigate the profile of young-adult apolipoprotein E (APOE) ɛ4 carriers across cognitive domains given that possession of this gene variant increases risk of developing dementia in later life. We also explored whether APOE genotype interacts with the cognitive enhancer, nicotine. A total of 1 mg of the cholinergic agonist nicotine was administered through nasal spray to healthy non-smoking young adults (aged 18–30) with either ɛ3/ɛ3 (N=29) or ɛ4 (at least one ɛ4 allele, N=27) genotype. Participants were matched on age, sex, and IQ in a placebo-controlled, double-blind 2 (drug: placebo, nicotine) × 2 (genotype: ɛ3, ɛ4) between subjects design. Here, we show that, paradoxically, possession of the ɛ4 allele confers a cognitive advantage on tasks mediated by the frontal lobe, and that young carriers of the ɛ4 allele show larger cognitive benefit from procholinergic nicotinic stimulation. These results are the first to show that genetic differences influence the efficacy of a cognitive enhancer.
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Acknowledgements
This work was supported by a Sussex University D.Phil. studentship and an Overseas Research Scheme Award to the first author. We thank McNeil AB, Helsingborg, Sweden for providing the nasal sprays.
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Naji Tabet has received research grants (unrelated to this study) from Pfizer and Novartis. He also received consultation and/or speaker fees from Pfizer, Eli Lilly, AstraZenca, Shire, Novartis, and Lundbeck. Natalie Marchant, Sarah King, and Jennifer Rusted have no conflicts of interest to disclose.
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Marchant, N., King, S., Tabet, N. et al. Positive Effects of Cholinergic Stimulation Favor Young APOE ɛ4 Carriers. Neuropsychopharmacol 35, 1090–1096 (2010). https://doi.org/10.1038/npp.2009.214
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DOI: https://doi.org/10.1038/npp.2009.214
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