Background
Aging was recently described as a “neurocatastrophe” involving increased oxidative stress, disturbed energy homeostasis, accumulation of damaged proteins, and lesions in nucleic acids, making aging the primary risk factor for development of neurodegenerative diseases. Age-related diseases constitute a huge burden for individuals and societies and problems are likely to grow as the proportions of the population vulnerable to these diseases increase.

 Fortunately, progress has been made in the understanding of factors underlying individual differences in cognitive and brain aging and the rapid rise of knowledge and technology in molecular genetics and steeply decreasing costs of genetic sequencing have made it an achievable endeavor to start identifying the genes in the central nervous system that influence human brain and cognition. Genomic variation, such as single nucleotide polymorphisms (SNPs), gives rise to rich phenotypic variation, holding the promise to substantially increase understanding of the biology of brain and cognitive aging. In our group, we focus on genes related to neuronal health and plasticity such as apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and neurotransmission genes related to catecholaminergic and cholinergic function, (e.g. CHRNA4). A recent focus of interest is genes related to repair of age-related DNA damage (see below). We make use of a rich array of methods including advanced genotyping techniques, tailor-made behavioral assays, event-related potentials, and structural and functional magnetic resonance imaging. The biobank includes blood samples, MRI-scans, and ERP- and cognitive data for healthy volunteers in the age range 20-75 years. As of September 2007 the biobank contains analyzed data from 500 participants. Further goals are to expand the range of data for all phenotype levels, and to follow up part of the group over time.
Our general aim is to advance the understanding of genetic modulation of brain and cognitive aging. The data generated by our projects will potentially be informative to at least three areas of research:
1) Development of Alzheimer’s disease and other neurodegenerative disorders; 2) Cognitive neuroscience of normal aging; and 3) Cognitive neurogenetics generally in which the aim is to understand the molecular mechanisms underlying cognitive processes such as memory, attention, and decision making.

Selection of published results
Several sets of interesting findings have so far emerged from our work. For example, in a study involving participants with subjective memory complaints aged 50-75, carriers of the Alzheimer’s disease susceptibility gene APOE ε4 showed lower amplitudes on components elicited by auditory stimuli (Reinvang et al., 2005). There was also a genotype dose effect such that carriers of two ε4 alleles were more affected than carriers of only one risk allele. Preliminary results from subsequent work indicate that this effect also appears in asymptomatic participants of the same age. Interestingly, CHRNA4 seems to modulate early latency potentials in both auditory and visual modalities (see Espeseth et al., 2007)
In a study of 96 healthy individuals (age range 45-75) for whom both structural MRI and APOE genotype data were available, analyses of cortical thickness showed that individuals with the ε4 allele had accelerated thinning of cortex in areas that typically show effects of normal aging (see figure). At the same time, ε4 carriers also had cortical thinning in occipito-temporal typically areas affected in AD (see Espeseth et al. in press). These results are preliminary and need to be interpreted with caution, but they are potentially significant. We have now obtained MRI data from younger participants as well and will get longitudinal data on the original group within the coming year.

Given the centrality of the “cholinergic hypothesis” in aging and AD research, it is of great interest to know whether APOE and cholinergic genes interact to influence attentional function and possibly age-related changes in these functions. We tested this hypothesis and found that the already identified ε4 attentional phenotype was potentiated for individuals who were also CHRNA4 T homozygotes, but attenuated for C homozygotes and TC heterozygotes (see Espeseth et al., 2006).

DNA repair genes and DNA damage related to oxidative stress
In a recent development of the project we collaborate with Tone Tønjum’s lab at CMBN in age-related DNA damage and individual differences in DNA repair efficiency. DNA damage is to a large extent mediated by the reactive oxygen species (ROS) which is formed as by-products of normal cellular metabolism, genotoxic chemicals, and ionizing radiation. Oxidative damage is one of the key mechanisms affecting cellular aging and human longevity, and is also related to the mitochondrial respiratory chain. One of the most frequent forms of oxidative DNA damage is the oxidation product of guanine, 8oxoG (GO), which can lead to base mispairing during DNA replication. ROS can induce mitochondrial and nucleic DNA lesions involving 8-oxoG. The base excision repair (BER) pathway is probably the cell’s most important line of defense against the deleterious effects of such DNA damage. BER involves among other processes, the release of modified base residues from DNA by DNA glycosylases, and incision of new bases by DNA polymerases. We seek to identify rate limiting factor processes in BER and search for genetic polymorphisms in the genes coding for these proteins deemed likely to influence structural or functional phenotypes.

Core team
Ivar Reinvang, Department of Psychology, University of Oslo
Thomas Espeseth, Department of Psychology, University of Oslo
Johanna Lind, Department of Psychology, University of Oslo

Collaborators
Anders M. Fjell & Kristine B. Walhovd, Department of Psychology, University of Oslo
Tone Tønjum & Tonje Davidsen, Center for Molecular Biology and Neuroscience, University of Oslo
Raja Parasuraman & Pamela M. Greenwood, George Mason University, USA
Helge Rootwelt, Department of Medical Biochemistry, Rikshospitalet-Radiumhospitalet Medical Center
Vidar M. Steen, Department of Human Genetics, University of Bergen
Arvid Lundervold, Department of Physiology, University of Bergen
Astri J. Lundervold, Department of Psychology, University of Bergen