Aging and dementia in Down syndrome

Down syndrome (DS) is a genetic disorder caused by full or partial triplication of chromosome 21 (HSA21). HSA21 incorporates genes related to Alzheimer disease (AD) causing early onset of AD pathology, followed by clinical dementia, and reduced life expectancy. Triplication of the HSA21 gene, amyloid precursor protein, drives accumulation of amyloid beta (Aβ) in the brain. This accumulation is proposed to promote neurofibrillary tangle (NFT) accumulation. Aβ and NFT are key features of AD neuropathology. Almost all individuals with DS aged 40 years and older have significant Aβ and NFT brain accumulation; however, a clinical diagnosis of dementia is generally delayed by a decade or more. The interval between accumulating Aβ and NFT pathologies and the emergence of clinical symptomatology can be described as a preclinical stage with minimal or subtle symptoms that are often not readily detected with current clinical measures. Recent research demonstrates structural and functional neuroimaging changes that are linked to Aβ and NFT accumulation as well as contributions of cerebrovascular disease to dementia in DS. However, given the genetic complexity of HSA21, more work is needed to understand these genotypic contributors. Additionally, clinical tools to improve diagnostic accuracy and earlier dementia detection are important foci for research to identify potential interventions to address the progression of AD in DS.