Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer's pathology

The APOE-ε4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-ε4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1β, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau₁₈₁ and amyloid-β_1-42 (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-ε4 genotype. This suggests that APOE-ε4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD.