Neurogenetics of aging and Alzheimer's disease: impact of DNA repair

Considering the expanding numbers of elderly in our society, studies of health and disease in the aging population is increasingly important. Age is the major risk factor of Alzheimer’s disease (AD). In order to understand AD, one must understand normal aging. One of the main theories of aging is based on the notion that macromolecular damage of DNA accumulates over time. These events could cause many of the phenotypical changes and genome instability seen with the aging process and neurodegenerative diseases such as AD. A particular culprit in this context is oxidative stress. To counteract the potential harmful effects of genotoxic stress, organisms have established an array of repair systems and base excision repair (BER) is the major pathway for repairing oxidative DNA damage. In this study, we aimed to elucidate the role of DNA repair in aging and AD, with a focus on BER. Our results from a cohort of 712 healthy individuals reveal association between the non-synonymous single nucleotide polymorphisms (SNP) hOGG1Ser326Cys and APE1Gln51His with cognitive performance. In an AD mouse model, we demonstrate differences in the expression of BER genes OGG1, APE1, Polβ and PARP1 in brain tissues between Tg-ArcSwe and wildtype (wt) mice as well as during the lifespan of both the Tg-ArcSwe and the wt mice. Thus, BER gene expression patterns may reflect DNA repair responses to oxidative stress with age and Aβ pathology. However, it remains a conundrum whether oxidative stress and altered DNA repair are consequences of AD pathology or represent antecedent contributors. Our study on AD patients shows association between hOGG1 and PARP1 expression in blood and cerebrospinal fluid (CSF) biomarkers in the prodromal stages of AD. Further, we found association of SNPs with cognitive performance (MMSE) and CSF biomarkers for AD. Collectively, these results establish a role for DNA repair in aging, for the first time linking the analysis of AD CSF biomarkers with DNA repair, expanding the pool of potential biomarkers for pre-clinical AD.