Abstract INTRODUCTION Development of Alzheimer's disease (AD) pathology in Down's syndrome (DS) occurs within a compressed timeline compared to sporadic or other genetic forms of AD. METHODS Plasma glial fibrillary acidic protein (GFAP) and plasma pTau‐217 levels were compared by AD pathophysiology (amyloid (A+) and tau (T+) positron emission tomography [PET]) in persons with DS ( N = 348) and sibling controls ( N = 42). Plasma GFAP, plasma pTau‐217, amyloid‐PET, and tau‐PET levels were compared with regard to estimated years to onset of clinical symptoms (52.5 years old). We evaluated if plasma GFAP mediated the relationship between amyloid PET and plasma pTau‐217 or tau PET. RESULTS Plasma GFAP, a measure of astrogliosis, was elevated in A+/T‐ and A+/T+ individuals with DS. Plasma pTau‐217 was elevated in A+/T+ individuals with DS. GFAP partially mediated the relationship between amyloid‐PET and tau‐PET (15.3%) and amyloid‐PET and plasma pTau‐217 (42.1%). DISCUSSION Astrogliosis is a key component in the advancement of preclinical AD pathophysiology in DS. Highlights Amyloid may be a necessary precursor for stimulating astrocytes. Astrogliosis may play a key role in modifications to tau phosphorylation. Targeting neuroinflammation may only aid amyloid positive individuals. Alzheimer's disease timecourse is compressed in individuals with Down's syndrome.

The mediating role of plasma glial fibrillary acidic protein in amyloid and tau pathology in Down's syndrome