PGRN Counteracts the Associations of Abnormal Tau Proteins with Neurodegeneration and Cognitive Decline in Non-demented Adults: A Longitudinal Study

Abstract

Abnormal tau proteins are characterized by accumulation of abnormally phosphorylated tau followed by irreversible loss of neurons. Progranulin (PGRN) is a secreted pleiotropic glycoprotein against the development of multiple neurodegenerative diseases. However, it remains unclear whether PGRN could modulate the relationships of abnormal tau proteins with cognition and neurodegeneration. A total of 606 non-demented participants were followed for 8 years and were annually assessed for cognition and brain volumes. Abnormal tau protein (TN) status was determined by cerebrospinal fluid (CSF) levels of P-tau₁₈₁ (T) or total tau (N) proteins. Linear mixed effects regressions were used to test the associations of PGRN × TN interaction with cognitive decline and brain atrophy rate, after adjusting for age, gender, education, APOE ε4, cognitive diagnosis, and amyloid pathology. TN ( +) was associated with faster cognitive decline and brain atrophy. The interaction term of PGRN × TN accounted for a significant amount of variance in cognitive decline (χ² = 9.667, p = 0.002 for memory, χ² = 13.229, p = 0.0003 for executive function) and brain atrophy (χ² = 9.626, p = 0.002 for hippocampus; χ² = 8.526, p = 0.003 for middle temporal region; χ² = 5.754, p = 0.016 for entorhinal cortex). The rates of cognitive decline and brain atrophy associated with abnormal tau proteins were suppressed in groups with higher levels of CSF PGRN. We firstly revealed that PGRN moderated the relationships of abnormal tau proteins with cognitive decline and brain atrophy. These findings suggested that the protective roles of PGRN in fighting against neurodegeneration could be partially via interaction with tau proteins.

Keywords: Alzheimer’s disease; Cognition; Interaction; Neurodegeneration; PGRN; TN pathology.