Cerebrospinal fluid p62/SQSTM1 is associated with tau pathology, brain structural alterations, and cognitive impairment in adults without dementia

Background The involvement of cerebrospinal fluid (CSF) Sequestosome-1 (SQSTM1, commonly known as p62), an autophagy-related scaffold protein, in Alzheimer's disease (AD) pathogenesis is not well established in human populations. Objective To investigate the associations of baseline CSF p62/SQSTM1 levels with cognitive function, AD biomarkers, brain structure, and incident dementia in non-demented individuals. Methods We included 557 dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative cohort. Multivariate regression and interaction analyses examined associations of CSF p62/SQSTM1 with cognition, AD biomarkers, and brain volumes and their modification by age, sex, APOE genotype, and diagnostic status. Kaplan-Meier and Cox analyses assessed dementia-free survival and incident dementia risk. Mediation analysis tested whether AD pathology and brain structure mediated the association between p62/SQSTM1 and cognition. Results Elevated CSF p62/SQSTM1 levels correlated with poorer cognition, heightened tau pathology, increased sTREM2 and PGRN levels, and decreased whole-brain and fusiform gyrus volumes. Age modified p62/SQSTM1 associations with cognition and whole-brain volume. Subgroup analyses revealed that significant associations between p62/SQSTM1 and cognitive function (MMSE, MEM) were primarily observed in the middle-aged group. Longitudinal analyses further showed that participants in the highest quartile (Q4) exhibited an increased risk compared to the lowest (Q1) (HR = 1.78, 95% CI 1.16–2.73). Mediation analysis indicated that tau pathology and reduced brain volumes mediated the association between p62/SQSTM1 and cognition. Conclusions Higher p62/SQSTM1 levels were associated with tau pathology and an elevated risk of AD. Tau-related pathological changes and brain structural alterations might be involved in the relationship between the p62/SQSTM1-related autophagy processes and cognition.