Alzheimer's disease (AD) is a neurodegenerative disorder with a complex etiology and pathogenesis. Chromosome missegregation was proposed two decades ago to be responsible for neurodegeneration in AD patients. It was speculated that the aneuploidy is a result of aberrant cell cycle of neuronal progenitors during adult neurogenesis and/or of mature neurons. There is mounting evidence of increased rate of general aneuploidy and cell cycle reentry in the AD patients' brains, with area-specific pattern. In this review, we discuss the involvement of chromosome instability, genome damage and cell cycle impairment in AD pathology.