Cholinergic System Structure and Function Changes in Individuals with Down Syndrome During the Development of Alzheimer's Disease.

Adults with Down syndrome represent the population with the highest risk of developing Alzheimer's disease worldwide. The cholinergic system is known to decline in Alzheimer's disease, with this decline responsible for many of the cognitive deficits that develop. The integrity of the cholinergic system across the lifespan in individuals with Down syndrome is not well characterized. Small fetal and infant post-mortem studies suggest an intact cholinergic projection system with a potential reduction in cholinergic receptors, while post-mortem studies in adults with Down syndrome reveal an age-related decrease in cholinergic integrity. Advances in magnetic resonance imaging (MRI) and positron emission tomography (PET) over the last 20 years have allowed for studies investigating the changes in cholinergic integrity across aging and during the development of Alzheimer's disease. One large cross-sectional study demonstrated reduced cholinergic basal forebrain volume measured by MRI associated with increasing Alzheimer's disease pathology. In a small cohort of adults with Down syndrome, we have recently reported that PET measures of cholinergic integrity negatively correlated with amyloid accumulation. New disease-modifying treatments for Alzheimer's disease and treatments under development for Alzheimer's disease in Down syndrome have the potential to preserve the cholinergic system, while treatments targeting the cholinergic system directly may be used in conjunction with disease-modifying therapies to improve cognitive function further. A greater understanding of cholinergic neuronal and receptor integrity across the lifespan in individuals with Down syndrome will provide insights as to when targeting the cholinergic system is an appropriate therapeutic option and, in the future, maybe a valuable screening tool to identify individuals that would most benefit from cholinergic interventions.