Additive genetic effect of APOE and BDNF on hippocampus activity
Introduction
Human memory, as cognition in general, has a heritability estimate of around 50% (McClearn et al., 1997), and a pattern of inheritance that includes heterogeneity, epistasis, gene–environment interactions, and additive effects of many genes with small individual effects (Papassotiropoulos and de Quervain, 2011). In order to reveal the genetics behind complex phenotypes, the importance of studying combined gene effects has been emphasized (de Quervain and Papassotiropoulos, 2006, Rasch et al., 2010, Schott et al., 2006, Smolka et al., 2007). Due to the small effect sizes of individual gene variants, few candidate genes have shown a consistent effect on cognitive measures and disease traits. Brain activation has been used as an intermediate phenotype between genes and behavior, typically yielding larger and more replicable effects than behavioral traits (Rasch et al., 2010). In addition, valuable information about the mechanisms in the chain from genes to behavior can be attained by examining gene effects on brain responses (Meyer-Lindenberg, 2012, Papassotiropoulos and de Quervain, 2011, Rasch et al., 2010).
The hippocampus and the parahippocampal gyrus within the medial temporal lobe (MTL) are highly important for human learning and memory (Eichenbaum, 2004). These regions have also been implicated in several neuropsychiatric disorders such as Alzheimer's disease (AD) (Small et al., 1999), bipolar disease (Chen et al., 2011), and schizophrenia (Weinberger, 1999). Memory-related activation of the hippocampus, as a proxy for hippocampus function, has been successfully used as an intermediate phenotype to study genes with a role in episodic memory as well as disorders linked to hippocampal dysfunction (Rasch et al., 2010). Considering the complex pattern of inheritance for those phenotypes, it is of great interest to study the combined effect of more than one gene on functional brain responses in the MTL. However, the impact of most candidate genes has still only been studied in isolation (but see for example de Quervain and Papassotiropoulos, 2006). Two of the individually most studied candidate genes for memory, as well as dementia and other neuropsychiatric diseases, are apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF).
The APOE ε4 allele is the strongest known genetic risk factor for late-onset AD (Verghese et al., 2011). APOE is involved in lipid homeostasis, in particular cholesterol levels, and also influences the risk for cardiovascular disease (Wilson et al., 1996). The mechanisms behind the relation of APOE with cognition as well as with AD are not fully understood, but there is evidence that the isoforms of APOE differentially modulate the metabolism and accumulation of amyloid-β (Corder et al., 1993, Verghese et al., 2011). The accumulation of amyloid-β plaques is assumed to be involved in the pathology of AD. There are three isoforms of APOE present in the population; the ε2, ε3 and ε4 alleles, of which the ε3 allele is most common and ε2 least common. The presence of one or two ε4 alleles increases the risk to develop AD in a dose-dependent manner, and is associated with earlier onset of the disease (Blacker et al., 1997, Corder et al., 1993, Farrer et al., 1997). The ε4 allele is also related to increased risk for mild cognitive impairment (MCI), decreased longevity and accelerated cognitive decline during normal aging (Bretsky et al., 2003, Dik et al., 2000, Smith, 2002).
BDNF has an important role in learning and memory by being produced on demand upon neural activity to stimulate neuronal and synaptic growth and differentiation (Egan et al., 2003, Poo, 2001). Val66Met is a functional single nucleotide polymorphism (SNP) in the 5′ pro-BDNF sequence, of which the Met allele has been related to diminished activity-dependent secretion of BDNF in neurons (Egan et al., 2003). BDNF Val66Met has also been related to various neuropsychiatric disorders, such as schizophrenia (Neves-Pereira et al., 2005), bipolar disorder (Neves-Pereira et al., 2002), and Alzheimer's disease (Fehér et al., 2009), although the results have not been consistent (Hong et al., 2011).
Recent meta-analyses showed that both the APOE ε4 (Wisdom et al., 2011) and the BDNF Met (Kambeitz et al., 2012) alleles are related to lower memory performance in non-demented participants, at least in the upper adulthood. In relation to hippocampal functioning, we previously reported decreased parahippocampal activation in a large number of healthy carriers of the BDNF Met allele (Kauppi et al., 2013). Similar findings have been demonstrated in two other smaller samples (Hariri et al., 2003, Hashimoto et al., 2008). Regarding APOE, brain imaging results have been more conflicting, with both decreased (Adamson et al., 2011, Lind et al., 2006, Trivedi et al., 2006) and increased (Bookheimer et al., 2000, Filippini et al., 2009, Han et al., 2007) hippocampal activation in ε4 carriers.
Both APOE and BDNF play important roles in memory and hippocampal functioning. A previous study failed to find an interaction between APOE and BDNF on hippocampal volume and memory performance (Richter-Schmidinger et al., 2011), but to our knowledge their combined effect on brain activation has not been examined. The aim of the current study was therefore to investigate the combined effect of APOE ε4 and BDNF Met on memory related brain activation in the MTL. Since we have recently reported single-gene analyses of BDNF on brain activation in this population (Kauppi et al., 2013), we provide a corresponding single-gene analysis also for APOE (Supplementary materials). Here, we hypothesized diminished medial–temporal activation in APOE ε4 carriers relative to ε3 homozygotes, as we have previously found decreased activation in carriers of a low-memory associated allele in both BDNF (Kauppi et al., 2013) and KIBRA (Kauppi et al., 2011) in this dataset. For APOE × BDNF combined gene analyses, we tested both for 2-by-2 gene–gene interactions, as well as for an additive relation between hippocampal activation and the number (0, 1, 2) of APOE ε4 and BDNF Met alleles.
Section snippets
Participants
All participants belong to a larger fMRI study performed on 376 individuals recruited from the Betula study (Kauppi et al., 2011, Nilsson et al., 2004). From this sample, genotype data on APOE and BDNF were available for 293 participants in six age groups; 55, 60, 65, 70, 75, and 80 years. Sixty-eight participants were excluded based on behavioral criteria (pre-defined as < 50% retrieval responses and/or < 10 out of 24 correct responses, and/or incorrect task performance and/or self-reported
Single-gene analyses
Results from single-gene analyses of APOE are presented in detail in the Supplementary materials. There were no behavioral differences between APOE genotypes, and the groups were comparable for the examined demographic variables. APOE ε4 carriers had significantly lower encoding-related activation in the right MTL than individuals with the ε3/ε3 genotype.
Behavioral results
The ANOVA and Chi2 tests, respectively, revealed no significant differences in age, task performance, MMSE, gender frequency, or family
Discussion
The current results demonstrate that brain activation in the MTL during memory processing is additively decreased by the presence of the APOE ε4 and the BDNF Met alleles. The strongest activation was seen in noncarriers of both APOE ε4 and BDNF Met, intermediate activation in carriers of one of the alleles, and lowest activation in carriers of both of these “low-memory associated alleles”. The combined gene analyses revealed stronger effects, and larger clusters of activation, than the
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the Swedish Research Council and a Wallenberg Scholar Grant from the Knut and Alice Wallenberg Foundation (to L.N.). The Betula project is supported by a grant from the Swedish Research Council (315-2004-6977 to L.G.N. and L.N.). We thank Elias Eriksson, Rolf Adolfsson, and Christine Van Broeckhoven for DNA extraction and genotyping, the staff at Betula and Umeå Center for Functional Brain Imaging for data collection and Anders Lundquist for statistical consultations.
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Present address: Aging Research Center (ARC), Karolinska Institutet, Gävlegatan 16, SE-11330 Stockholm, Sweden and Department of Integrative Medical Biology (Physiology) Umeå University, SE-90187, Umeå, Sweden and Umeå Center for Functional Brain Imaging (UFBI), Umeå, Sweden.