Abstract
BACKGROUND: Autophagy has recently attracted increasing attention for its critical involvement in Alzheimer’s Disease (AD) pathogenesis. However, the role of microtubule-associated protein 1 light chain 3 A (LC3A) and B (LC3B), key autophagic-associated proteins in cognitive decline, AD risk, and underlying pathology remain unclear. METHODS: This study included 568 participants from the Alzheimer’s Disease Neuroimaging Initiative with cerebrospinal fluid (CSF) measurements of LC3A and LC3B. We systematically assessed the associations of LC3A and LC3B with cognition, dementia risk, AD biomarkers, microglial activity, brain volume, and metabolism through both cross-sectional and longitudinal analyses. Additionally, subgroup analyses based on ATN classification were conducted to evaluate stage-specific effects, and Receiver operating characteristic (ROC) analyses were employed to explore the clinical predictive value of LC3A and LC3B. Finally, mediation models were used to investigate the potential mechanisms by which LC3A and LC3B affect AD pathology and cognition. RESULTS: Elevated CSF LC3A and LC3B levels were negatively associated with cognition, while positively associated with amyloid deposition, total tau (t-tau), phosphorylated tau (p-tau), progranulin (PGRN), and soluble Triggering Receptor Expressed on Myeloid Cells-2 (sTREM2) at baseline. Higher CSF LC3A and LC3B concentrations were linked to an increased risk of dementia, accelerated longitudinal cognitive decline, greater brain atrophy, faster accumulation of t-tau, and longitudinal associations with sTREM2. Individuals with TN+ exhibited significantly higher CSF LC3A and LC3B levels compared to those with TN−. Moreover, CSF LC3A alone could predict TN−/TN+ status with an area under the curve (AUC) of 0.903, which increased to 0.939 when combined with amyloid PET. Similarly, CSF LC3B alone yielded an AUC of 0.876, rising to 0.913 when combined with amyloid PET. Finally, amyloid deposition and microglial activation individually or jointly, mediated the effects of LC3A and LC3B on tau pathology and cognitive decline. CONCLUSIONS: CSF LC3A and LC3B, reflecting autophagic activation, are linked to elevated tau pathology and an increased risk of AD. They may jointly contribute to AD pathological progression alongside amyloid deposition and microglial activation. LC3A and LC3B as robust candidate biomarkers for monitoring pathological burden, stratifying disease risk, and informing clinical evaluation in AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03758-7.