ε4 carrier controls showed increased proteins linked to blood-brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.<h4>Discussion</h4>Combining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.<h4>Highlights</h4>Apolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD). Here, APOE is linked to Alzheimer disease.