Background: Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with an ultra-high risk of developing Alzheimer’s disease. However, there is individual variability in the onset of clinical dementia and in baseline cognitive abilities prior to decline, particularly in memory, executive functioning, and motor coordination. The LonDownS Consortium aims to determine risk and protective factors for the development of dementia and factors relating to cognitive abilities in people with DS. Here we describe our cognitive test battery and related informant measures along with reporting data from our baseline cognitive and informant assessments. Methods: We developed a cognitive test battery to assess general abilities, memory, executive function, and motor coordination abilities in adults with DS, with informant ratings of similar domains also collected, designed to allow for data on a broad range of participants. Participants (n=305) had a range of ages and abilities, and included adults with and without a clinical diagnosis of dementia. Results: Results suggest the battery is suitable for the majority of adults with DS, although approximately half the adults with dementia were unable to undertake any cognitive task. Many test outcomes showed a range of scores with low floor and ceiling effects. Non-verbal age-adjusted IQ scores had lower floor effects than verbal IQ scores. Before the onset of any cognitive decline, females aged 16-35 showed better verbal abilities compared to males. We also identified clusters of cognitive test scores within our battery related to visuospatial memory, motor coordination, language abilities, and processing speed / sustained attention. Conclusions: Our further studies will use baseline and longitudinal assessments to explore factors influencing cognitive abilities and cognitive decline related to ageing and onset of dementia in adults with DS.

Key Points Question How does dementia status influence mortality in people with Down syndrome? Findings In a longitudinal study including 211 adults with Down syndrome 36 years and older, 27 people died during follow-up (mean, 28; range, 1-65 months), and dementia was the proximate cause of death in 70% of cases. Crude mortality rates were 5 times higher in those with dementia than those without. Meaning Nearly all older adults with Down syndrome now have dementia when they die, making this a vital population for researching disease progression, modifying factors, and potential treatments.

IntroductionDown syndrome (DS) is associated with an almost universal development of Alzheimer's disease. Individuals with DS are therefore an important population for randomized controlled trials to prevent or delay cognitive decline, though it is essential to understand the time course of early cognitive changes.MethodsWe conducted the largest cognitive study to date with 312 adults with DS to assess age-related and Alzheimer's disease–related cognitive changes during progression from preclinical to prodromal dementia, and prodromal to clinical dementia.ResultsChanges in memory and attention measures were most sensitive to early decline. Resulting sample size calculations for randomized controlled trials to detect significant treatment effects to delay decline were modest.DiscussionOur findings address uncertainties around the development of randomized controlled trials to delay cognitive decline in DS. Such trials are essential to reduce the high burden of dementia in people with DS and could serve as proof-of-principle trials for some drug targets.