APOE Genotype and Fluid Biomarkers of Blood-Brain Barrier Integrity: A Systematic Review and Meta-Analysis

Apolipoprotein E (APOE) genotype is theorised to influence dementia risk partly through effects on blood-brain barrier (BBB) function, but clinical studies examining APOE effects on BBB biomarkers report inconsistent results. Therefore, this systematic review and meta-analysis quantified associations between APOE genotype and two commonly used fluid biomarkers of CNS barrier function: cerebrospinal fluid (CSF)/serum albumin quotient (Q-Alb), and soluble platelet-derived growth factor receptor beta (sPDGFRB). Ovid MEDLINE, Embase, and Web of Science were searched on 30th June, 2026. Eligible peer-reviewed human studies reported Q-Alb or blood or CSF sPDGFRB; by APOE genotype. Risk of bias was assessed using the Joanna Briggs Institute checklist. Twenty-eight studies involving 5,375 participants were included: 17 assessed Q-Alb and 11 assessed sPDGFRB. Random-effects meta-analyses determined that APOE e2 carriage was associated with higher Q-Alb (g = 0.29, 95% CI 0.11 to 0.46). APOE e4 carriage was not associated with Q-Alb overall (g = .13, 95% CI -.17 to .43) or sPDGFRB overall (g = .10, 95% CI -.21 to .40). Genotype-specific Q-Alb analyses suggested medium positive but non-significant effects among e4/e4 and e2/e4 carrier subgroups. For sPDGFRB, exploratory subgroup analysis revealed effect estimates near zero in cognitively unimpaired participants, and a small positive non-significant effect in cognitively impaired participants. Larger effects were also observed in samples with an older mean age, although this was not statistically significant. Overall, evidence for APOE e4-associated alterations in Q-Alb and sPDGFRB remained inconclusive, highlighting the need for further study across the spectrum of cognitive ageing and dementia. In contrast, APOE e2 carriage was associated with greater barrier dysfunction as indexed by Q-Alb, broadening the predominant focus on APOE e4 and identifying e2 as a potentially important but understudied contributor to altered neurovascular function.