The accumulation of nonrepaired or misrepaired DNA lesions, induced by exogenous and/or endogenous DNA-damaging agents, has been postulated to be one of the major and fundamental causes of aging. The accumulation of DNA damage might lead to changes in the expression of genes important for cell survival and, as such, could be a relevant risk factor in the etiology of various age-related diseases, including neurodegenerative diseases. This review deals specifically with Alzheimer's disease (AD) and the proposed role of defective DNA repair in the etiology of this disease. The evidence that a genetic defect in some aspect of base excision repair is present in cells from AD patients is discussed. Based on the available data, it seems justified to conclude that in at least the familiar form of the disease such a DNA repair defect is present in fibroblast and lymphoid cells. The absence of sufficiently efficient DNA repair mechanisms, involved in the removal of small base damages in the brain, could result in the accumulation of misrepaired or nonrepaired DNA damage and might ultimately lead to the neuronal degeneration as observed in AD patients. In this respect, the existence of inherently imperfect DNA repair processes in longer-lived species, such as mammals, might be regarded as a trade-off between reproductive success and cellular maintenance and repair, which would lead to a high level of DNA damage and mutation at old age.
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