<h4>Background</h4>The relationship between plasma chaperone-related autophagy proteins and white matter hyperintensity (WMH) in Alzheimer's disease (AD) remains unclear.<h4>Methods</h4>We employed 4D-DIA proteomics to identify plasma protein changes, and evaluated the clinical relevance of the chaperone-mediated autophagy (CMA)-related protein HSPA8. This evidence concerns the gene HSPA8 and early-onset autosomal dominant Alzheimer disease.