Abstract
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.
Highlights
Down syndrome (DS), caused by trisomy of chromosome 21, has a UK incidence of approximately one in 1000 live births [1] and is associated with intellectual disability (ID) and an ultra-high risk of developing Alzheimer’s disease (AD) [2]
Age group showed the greatest effect size as determined using h2 values for measures from the paired associates learning (PAL), object memory, simple reaction time (SRT), and Developmental NEuroPSYchological Assessment-II explaining more than 30% of variance in scores for each outcome (Table 2)
Comparing the older age groups with those aged 1630 years (Table 3 and Supplementary Table 2), the earliest changes in performance were seen for the PAL first trial memory score and SRT latency standard deviation (SD), with significantly poorer performance starting in adults aged 41-45 years (P 5 .002 and P 5 .001, respectively)
Summary
Down syndrome (DS), caused by trisomy of chromosome 21, has a UK incidence of approximately one in 1000 live births [1] and is associated with intellectual disability (ID) and an ultra-high risk of developing Alzheimer’s disease (AD) [2]. The cumulative incidence of dementia has been suggested to be 95.7% by the age of 68 years with a mean age of diagnosis of 55 years [3], indicating cognitive decline is a near universal part of aging in DS.
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