Neurogenetics of attention in the aging brain

Aging was recently described as a ?neurocatastrophe? involving increased oxidative stress, disturbed energy homeostasis, accumulation of damaged proteins, and lesions in nucleic acids (Mattson & Magnus, 2006), making aging the primary risk factor for deve lopment 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 m ade in the understanding of factors underlying individual differences in cognitive and brain aging. Single nucleotide polymorphisms (SNPs) give rise to rich phenotypic variation, holding the promise to substantially increase understanding of the biology o f brain and cognitive aging. In the project proposed here, we focus on the genes encoding apolipoprotein E (APOE) and the DNA glycosylase MutY, neurotransmission genes related to catecholaminergic function, and cholinergic receptor and transporter genes. Disconnection theory posits that cognitive decline in aging is driven by progressive disconnection between neural nodes in the brain due to demyelination. An alternative account claims that cognitive decline is driven by dysfunction or structural deterior ation in localized cortical regions or subcortical structures. In close collaboration with top international expertise on molecular genetics, brain imaging and cognitive neurogenetics, the proposed project seeks to advance the understanding of genetic mod ulation of brain and cognitive aging, with a special emphasis on connectivity between anatomically distinct but functionally interdependent neural nodes as a possible mediating factor between genetic variation and attentional performance. Specifically, th e project will focus on genetic variation in genes conferring neuronal damage and repair mechanisms and how these systems interact with neurotransmission genes and attentional function.