Development of Molecular Neuropathology in Down Syndrome across the Lifespan

Down syndrome (DS) is a common and recognizable genetic condition. Altered neurodevelopmental programs caused by trisomy 21 lead to the hallmark intellectual disability in early life. The increased lifespan of individuals with DS in the latter half of the twentieth century revealed the emergence of Alzheimer's disease (AD) earlier and with a higher prevalence in individuals with DS than in the general population. Thus, neuropathology in DS progresses along a continuum from prenatal disruptions to the manifestations of age-related conditions and AD. This review discusses our current understanding of the mechanisms of altered neurodevelopment and the precocious onset of AD in DS. We highlight the gaps in our understanding of how neurodevelopment and neurodegeneration are linked and describe how advancements in molecular technology and computational modeling are revealing molecular neuropathology in DS across the lifespan.