AbstractBackgroundAlzheimer’s disease (AD) brains are characterized by extracellular amyloid‐beta (Aβ) deposition and autophagy dysregulation. Here we aimed at deepening the understanding of these brain pathologies and how they translate to the CSF using App knock‐in mice.MethodAD postmortem brain tissues and App knock‐in mouse models (AppNL‐F and AppNL‐G‐F ) were used for autophagy characterization. The cerebrospinal fluid (CSF) from App knock‐in mice was analyzed by label‐free mass spectrometry (MS) and compared with previously reported CSF MS results from patients. The expression of decorin in the mouse brains was analyzed by immunohistochemistry and western blot. The autophagy‐activating effect of decorin was measured in the mouse primary neurons.Resultp62 and LC3 II levels were increased in AppNL‐G‐Fmice similar to the marked accumulation of p62 in AD brains. Several extracellular matrix (ECM) proteins, including decorin, were significantly increased in the CSF of both AppNL‐F mice and amyloid‐positive/tau‐negative subjects with normal cognition. Decorin was decreased in parvalbumin‐positive interneurons but increased in choroideus plexus of AppNL‐Fmice, both of which correlated with Aβ pathology. Decorin‐treated mouse primary neurons exhibited lowered p62 and LC3 II levels.ConclusionAutophagy is similarly inhibited in the brains of AppNL‐G‐Fmice and AD patients. The similar increase of decorin in CSF of AppNL‐F mice and amyloid‐positive/tau‐negative subjects with normal cognition indicates a potential of decorin as an early biomarker of Aβ amyloidosis. In addition, decorin activates neuronal autophagy by increasing autophagosomal‐lysosomal degradation linking changes in ECM to autophagy.