High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer's disease

Abstract

Early-onset Alzheimer's disease (EOAD) is a rare devastating subclassification of Alzheimer's disease (AD). EOAD affects individuals <65 years old, and accounts for 5%-10% of all AD cases. Previous studies on EOAD primarily focused on familial forms, whereas research on sporadic EOAD (sEOAD), which represents 85%-90% of EOAD cases, is limited. In this prospective cohort study, participants were recruited between 2018 and 2023 and included patients with sEOAD (n = 110), late-onset AD (LOAD, n = 89), young controls (YC, n = 50), and older controls (OC, n = 25). All AD patients fulfilled the diagnostic criteria based on biomarker evidence. Familial EOAD patients or non-AD dementia patients were excluded. Single molecule array technology was used to measure fluid biomarkers, including cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ) 40, Aβ42, phosphorylated tau (P-tau) 181, total tau (T-tau), serum neurofilament light chain and glial fibrillary acidic protein (GFAP). Patients with sEOAD exhibited more severe executive function impairment and bilateral precuneus atrophy (P < 0.05, family-wise error corrected) than patients with LOAD. Patients with sEOAD showed elevated CSF and plasma P-tau181 levels (154.0 ± 81.2 pg/mL, P = 0.002; and 6.1 ± 2.3 pg/mL, P = 0.046). Moreover, precuneus atrophy was significantly correlated with serum GFAP levels in sEOAD (P < 0.001). Serum GFAP levels (area under the curve (AUC) = 96.0%, cutoff value = 154.3 pg/mL) displayed excellent diagnostic value in distinguishing sEOAD patients from the control group. These preliminary findings highlight the crucial role of tau protein phosphorylation in the pathogenesis and progression of sEOAD.

Keywords: Alzheimer’s disease; Early-onset Alzheimer’s disease; Familial hereditary; Phosphorylated tau; Precuneus.