Background:
Down syndrome (DS) is associated with an ultra-high risk of Alzheimer’s disease(AD): >85% of people with DS develop dementia by age 65. DS prevalence in Ireland, estimated to be 7,000 people, is amongst the highest in Europe. Disease-modifying-therapies (DMTs) promise to transform the lives of those with AD and could avert a looming public health crisis if found to slow AD in DS (DSAD). However, individuals with DS, despite being genetically predestined to develop AD, were excluded from clinical trials.
DSAD treatment trials are urgently needed but will bring design challenges. Traditional AD screening measures are invasive and expensive, while clinical heterogeneity complicates interpretation of cognitive testing. Blood biomarkers could have a transformative impact on the diagnosis of DSAD and the testing of treatments. However, blood biomarkers of DSAD must first achieve validation status, for which a number of steps remain outstanding.
Central hypothesis: Blood biomarkers can be used in DS to accelerate diagnosis and treatment of AD and advance understanding of pathophysiology.
Objectives:
to explore novel and targetable pathophysiological mechanisms by focusing on whether markers of altered type I interferon signalling (“Type I interferonopathy”)
differ between sporadic AD, autosomal dominant AD and DS AD
differ across disease stage: presymptomatic vs symptomatic disease DSAD and autosomal dominant AD
are associated with downstream measures of inflammation (cytokines, chemokines), AD pathology (p-tau217) and neurodegeneration (NfL, cognitive change)
to conduct a meta-analysis to determine the diagnostic accuracy of blood based biomarkers to detect DSAD
to determine biological variability of plasma biomarkers of AD pathology (p-tau217) and neurodegeneration (Neurofilament-Light (NfL)) in DS and controls by examining the stability of these analytes during a short-interval serial blood sampling study
to determine sample size estimates for clinical trials in DSAD by analysing multiple repeated measures of plasma biomarkers (p-tau217, NfL) over a range of intervals