Dynamic changes of CSF sPDGFRβ during ageing and AD progression and associations with CSF ATN biomarkers

Background: Loss of brain capillary pericyte is involved in the pathologies and cognitive deficits in Alzheimer's disease (AD). The role of pericyte in early stage of AD pathogenesis remains unclear. Methods: We investigated the dynamic changes of soluble platelet-derived growth factor receptor beta (sPDGFR beta) in cerebrospinal fluid (CSF), a marker of brain pericyte injury, in transition from normal ageing to early AD in a cognitively unimpaired population aged 20 to 90 years. Association between sPDGFR beta and ATN biomarkers were analyzed. Results: In lifetime, CSF sPDGFR beta continually increased since age of 20 years, followed by the increases of phosphorylated tau-181 (P-tau181) and total tau (T-tau) at the age of 22.2 years and 31.7 years, respectively; CSF A beta 42 began to decline since the age of 39.6 years, indicating A beta deposition. The natural trajectories of biomarkers suggest that pericyte injury is an early event during transition from normal status to AD, even earlier than A beta deposition. In AD spectrum, CSF sPDGFR beta was elevated in preclinical stage 2 and participants with suspected non-AD pathophysiologies. Additionally, CSF sPDGFR beta was positively associated with P-tau181 and T-tau independently of A beta 42, and significantly strengthened the effects of A beta 42 on P-tau181, suggesting that pericyte injury accelerates A beta-mediated tau hyperphosphorylation. Conclusions: Our results suggest that pericyte injury contributes to AD progression in the early stage in an A beta-independent pathway. Recovery of pericyte function would be a target for prevention and early intervention of AD.

Automated summary

This study found that pericyte injury plays an important role in the early stages of AD, even before A beta deposition. The study also found that CSF sPDGFR beta is positively associated with P-tau181 and T-tau, and accelerates A beta-mediated tau hyperphosphorylation. These results suggest that restoring pericyte function may be a target for prevention and early intervention of AD.