Down syndrome and Alzheimer's disease: A link between development and aging

A subset of aged individuals with Down syndrome (DS) exhibits the clinical features of Alzheimer's disease (AD) but our ability to detect dementia in this population is hampered by developmental differences as well as the sensitivity of existing test tools. Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated neuropathology is a consistent feature. This is due to the fact that trisomy 21 leads to a dose-dependent increase in the production of the amyloid precursor protein and subsequently the production of the amyloidogenic fragments leading to early and predominant senile plaque formation. A review of the existing literature indicates that oxidative damage and neuroinflammation may interact to accelerate the disease process particularly in individuals with DS over the age of 40 years. By combining clinical information with measures of brain-region specific neuropathology we can "work backwards" and identify the earliest and most sensitive clinical change that may signal the onset of AD. For the past 50 years, investigators in the fields of mental retardation, developmental disabilities, and aging have been interested in the curious link between AD and DS. The morphologic and biochemical origins of AD are seen in the early years of the lifespan for individuals with DS. Study of the process by which AD evolves in DS affords an opportunity to understand an important link between development and aging. This review will focus on advances in the molecular and clinical basis of this association.