Connections between Down Syndrome and the Development of Alzheimer's Disease

Abstract: Down syndrome (DS) results in a wide array of phenotypes due to triplication of human chromosome 21 (HSA21), including cognitive deficits, craniofacial abnormalities, increased risk of leukemia, and cardiovascular defects. DS is perhaps the most complex set of genetic anomalies that is consistently survivable, and it is the largest genetic cause of intellectual disability. HSA21 contains over 200 protein-coding genes and many non-coding elements that may alter gene expression across the genome, and dosage changes to certain genes are strongly linked with DS pathology. Importantly, individuals with DS exhibit widespread Alzheimer’s Disease (AD) pathology, and triplications of HSA21 genes such as APP, DYRK1A, and S100B exacerbate neurodegeneration as DS individuals age. These facets have been studied using mouse models that replicate pathological patterns observed in humans with DS. Both mouse models and DS individuals show stereotypic hallmarks of AD such as the formation of Aβ plaques and tau-based neurofibrillary tangles. Here, the shared mechanisms of DS and AD are discussed, with particular emphasis on biological pathways that are important for cognition, plasticity, and neural survival, including amyloid processing, tau pathology, neuroinflammation, and oxidative stress. Analysis of these factors suggests multiple common links between DS and AD, and understanding shared mechanisms will be key for improved diagnosis and treatment in these disparate, yet linked conditions.