PGRN Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating Neuroinflammation

Background: Both progranulin (PGRN) and neuroinflammatory activities increased over the course of Alzheimer’s disease (AD). In this study, we set out to determine if cerebrospinal fluid (CSF) PGRN could be a marker of neuroinflammation, and if so, how it contributed to AD pathogenesis and cognitive impairments. Methods: A total of 965 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped within the framework of A-T-N biomarker profile and clinical stage. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of neuroinflammatory markers on the associations of PGRN with amyloid burden indicated by CSF β-amyloid (Aβ) levels. The longitudinal influences of PGRN on cognition were tested. Results: Increases of CSF PGRN and multiple neuroinflammatory markers (sTNFR1, sTNFR2, TGF-β1, VCAM1, and ICAM1) were associated with tau-related neurodegeneration, but not with Aβ pathology. PGRN was positively linked with these neuroinflammatory markers only in the presence of tau pathologies (TN+). In TN+ profile, PGRN was associated with higher CSF Aβ42 via mediating neuroinflammatory markers and could also predict slower cognitive decline. The abovementioned associations became non-significant in TN- profile. Conclusions: PGRN could protect against Aβ pathology and cognitive impairments via modulating neuroinflammation that occurs with neuronal injuries.