Background: Down Syndrome (DS) is caused by trisomy of chromosome 21, which includes the gene for the amyloid precursor protein (APP) and leads to overproduction of beta-amyloid. Clinical-pathological studies indicate that individuals with DS begin demonstrating Alzheimer's disease (AD) pathology during adolescence and that 100% exhibit such changes by age 40. Individuals with DS therefore represent a highly enriched population for AD. Additionally, owing to their baseline intellectual disability, people with DS represent a more vulnerable group of individuals as compared with other populations. Given the recent developments in AD biomarkers, combined with the prospect of achieving greater efficacy with earlier therapeutic intervention, it is logical to include adults with DS in prevention trials for AD.
Discussion: The US Food and Drug Administration has released draft guidance on drug development for early-stage AD, based on the understanding that AD is a progressive disease with symptoms developing decades after the disease process has begun. New biomarkers now permit detection of AD pathology in asymptomatic individuals such that there now exists an opportunity to conduct clinical trials of potentially disease-modifying drugs in the earliest stages of the disease and perhaps have the greatest chance of demonstrating efficacy. As such, clinical trials are being actively planned or conducted in individuals with causative mutations in the APP, presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes.
Summary: Individuals with DS comprise perhaps the largest group of people with genetically determined AD, with a worldwide population of about 6 million people. Only by inclusion can we provide access to rational therapies that offer the greatest chance of benefiting this highly at-risk population.