► Whole chromosome aneuploidy is a common feature observed in the development of the mammalian nervous system. ► Aneuploidy is a mechanism that could generate genetic diversity. ► Aneuploidy is observed in the adult brain but at lower frequency then during development. ► Aneuploidy has been shown to be associated to neurodegenerative disorders and age related syndromes. Mechanisms that govern genome integrity and stability are major guarantors of viability and longevity. As people age, memory and the ability to carry out tasks often decline and their risk for neurodegenerative diseases increases. The biological mechanisms underlying this age-related neuronal decline are not well understood. Genome instability has been implicated in neurodegenerative processes in aging and disease. Aneuploidy, a chromosome content that deviates from a diploid genome, is a recognized form of genomic instability. Here, we will review chromosomal aneuploidy in the aging brain, its possible causes, its consequences for cellular homeostasis and its possible link to functional decline and neuropathies.