Opposing patterns of blood-brain barrier permeability and Alzheimer's disease biomarkers across APOE genotype.

APOE is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), influencing both proteinopathies and cerebrovascular integrity. While the ε4 allele is well studied, the role of ε2—particularly in relation to blood-brain barrier (BBB) permeability—remains underexplored. To investigate the association between APOE genotype, BBB permeability, and AD pathology in a large cohort of biomarker-confirmed AD patients. We analyzed data from 895 patients with a CSF-based diagnosis of AD. APOE genotype was determined, and patients were grouped as ε2 (n = 68), ε3 (n = 481), or ε4 carriers (n = 346). CSF Aβ42, p-tau181, t-tau, p-tau181/Aβ42 and QAlb (a marker of BBB permeability) were measured. Group comparisons were conducted using non-parametric tests with Holm-corrected post-hoc analyses. APOE ε4 carriers exhibited higher p-tau181/Aβ42, consistent with greater AD pathology. In contrast, APOE ε2 carriers showed higher QAlb values and lower p-tau181/Aβ42, suggesting increased BBB permeability despite lower disease burden. Our findings support a potential protective role of APOE ε2 associated with BBB permeability modulation. Further research is warranted to clarify mechanisms linking BBB permeability and disease burden in AD.