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Additive genetic effect of APOE and BDNF on hippocampus activity
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
Department of Psychology, Stockholm University,106 91 Stockholm, Stockholm Brain Institute, Sweden.
Aging Research Center (ARC), Karolinska Institutet, Gävlegatan 16, SE-11330 Stockholm, Stockholm University, Sweden.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
2014 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 89, no 1, 306-313 p.Article in journal (Refereed) Published
Abstract [en]

Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF.

Place, publisher, year, edition, pages
2014. Vol. 89, no 1, 306-313 p.
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-86666DOI: 10.1016/j.neuroimage.2013.11.049ISI: 000332057400029PubMedID: 24321557Scopus ID: 2-s2.0-84892892084OAI: oai:DiVA.org:umu-86666DiVA: diva2:700253
Note

Originally included in thesis in manuscript form.

Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Genes to remember: imaging genetics of hippocampus-based memory functions
Open this publication in new window or tab >>Genes to remember: imaging genetics of hippocampus-based memory functions
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the field of imaging genetics, brain function and structure are used as intermediate phenotypes between genes and cognition/diseases to validate and extend findings from behavioral genetics. In this thesis, three of the strongest candidate genes for episodic memory, KIBRA, BDNF, and APOE, were examined in relation to memory performance and hippocampal/parahippocampal fMRI blood-oxygen level-dependent (BOLD) signal. A common T allele in the KIBRA gene was previously associated with superior memory, and increased hippocampal activation was observed in noncarriers of the T allele which was interpreted as reflecting compensatory recruitment. The results from the first study revealed that both memory performance and hippocampal activation at retrieval was higher in T allele carriers (study I). The BDNF 66Met and APOE ε4 alleles have previously been associated with poorer memory performance, but their relation to brain activation has been inconsistent with reports of both increased and decreased regional brain activation relative to noncarriers. Here, decreased hippocampal/parahippocampal activation was observed in carriers of BDNF 66Met (study II) as well as APOE ε4 (study III) during memory encoding. In addition, there was an additive gene-gene effect of APOE and BDNF on hippocampal and parahippocampal activation (study III). Collectively, the results from these studies on KIBRA, BDNF, and APOE converge on higher medial temporal lobe activation for carriers of a high-memory associated allele, relative to carriers of a low-memory associated allele. In addition, the observed additive effect of APOE and BDNF demonstrate that a larger amount of variance in BOLD signal change can be explained by considering the combined effect of more than one genetic polymorphism. These imaging genetics findings support and extend previous knowledge from behavioral genetics on the role of these memory-related genes.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. 84 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1580
Keyword
Imaging genetics, fMRI, Episodic memory, SNP, KIBRA, BDNF, APOE, Hippocampus, Parahippocampus
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-71141 (URN)978-91-7459-598-7 (ISBN)978-91-7459-597-0 (ISBN)
Public defence
2013-06-14, BiA 201, Biologihuset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2013-05-24 Created: 2013-05-20 Last updated: 2015-04-30Bibliographically approved

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