Date Published: February 1, 2019
Publisher: Elsevier, Inc
Author(s): Carla M. Startin, Sarah Hamburg, Rosalyn Hithersay, Tamara Al-Janabi, Kin Y. Mok, John Hardy, Andre Strydom.
•Cognitive changes with aging in DS are likely due to the progression of AD.•Memory and attention show the earliest cognitive decline, from the early 40s.•Memory abilities show the greatest sensitivity to dementia development.•Modest sample sizes are sufficient for RCTs to prevent/delay dementia in DS.
Down syndrome (DS), caused by trisomy of chromosome 21, has a UK incidence of approximately one in 1000 live births  and is associated with intellectual disability (ID) and an ultra-high risk of developing Alzheimer’s disease (AD) . 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 , indicating cognitive decline is a near universal part of aging in DS. This increased dementia risk is driven by the overexpression of genes on chromosome 21, in particular the amyloid precursor protein (APP) gene; deposits of its protein product, amyloid-β, are a characteristic feature of AD and are found in the brains of adults with full trisomy 21 by the mid-30s , . DS may therefore be viewed as a genetic cause of AD alongside known autosomal dominant pathogenic mutations in the APP, presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes (autosomal dominant AD [ADAD]) , although the clinical course during the early stages of AD in DS is less well described .
We have investigated cross-sectional changes in cognitive abilities associated with AD development in over 300 adults with DS. Memory and attention measures were most sensitive to aging, with significantly poorer performance starting in the early 40s. Similarly, performance for memory and attention outcomes was most sensitive to progression from preclinical to prodromal dementia, whereas performance for memory outcomes was most sensitive to progression from prodromal to clinical dementia. Using outcomes identified as sensitive to AD progression, we estimated possessing an APOE ε4 allele accounted for approximately 8% of variance in scores, and modest sample sizes would be sufficient to detect a significant treatment effect to delay cognitive decline in an RCT.