Neuroinflammation modulates the association of PGRN with cerebral amyloid-β burden

Progranulin (PGRN) and neuroinflammatory markers increased over the course of Alzheimer's disease (AD). We aimed to determine whether neuroinflammation could modulate the association of PGRN with amyloid pathologies. Baseline cerebrospinal fluid (CSF) PGRN and AD pathologies were measured for 965 participants, among whom 228 had measurements of CSF neuroinflammatory markers. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects within the framework of A/T/N biomarker profile. Increased levels of CSF PGRN and inflammatory markers (sTNFR1, sTNFR2, TGF-β1, ICAM1, and VCAM1) were associated with T- or N-positive (TN+) profile, irrespective of the amyloid pathology. In TN+ group, CSF PGRN was associated with increased levels of these inflammatory markers and CSF amyloid-β_1-42 (p < 0.01). The neuroinflammatory markers significantly modulated (proportion: 20%~60%) the relationship of amyloid burden with CSF PGRN, which could predict slower cognitive decline and lower AD risk in the TN+ group. The abovementioned associations became non-significant in the TN- group. These findings revealed a close relationship between neuroinflammation and CSF PGRN in contributing to AD pathogenesis, and also highlighted the specific roles of PGRN in neurodegenerative conditions. Future experiments are warranted to verify the causal relationship.