APOE Genotype and Fluid Biomarkers of Blood-Brain Barrier Integrity: A Systematic Review and Meta-Analysis
- 1La Trobe University
Abstract
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 (sPDGFR{beta}). 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 sPDGFR{beta} 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 sPDGFR{beta}. Random-effects meta-analyses determined that APOE {varepsilon}2 carriage was associated with higher Q-Alb (g = 0.29, 95% CI 0.11 to 0.46). APOE {varepsilon}4 carriage was not associated with Q-Alb overall (g = .13, 95% CI -.17 to .43) or sPDGFR{beta} overall (g = .10, 95% CI -.21 to .40). Genotype-specific Q-Alb analyses suggested medium positive but non-significant effects among {varepsilon}4/{varepsilon}4 and {varepsilon}2/{varepsilon}4 carrier subgroups. For sPDGFR{beta}, 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 {varepsilon}4-associated alterations in Q-Alb and sPDGFR{beta} remained inconclusive, highlighting the need for further study across the spectrum of cognitive ageing and dementia. In contrast, APOE {varepsilon}2 carriage was associated with greater barrier dysfunction as indexed by Q-Alb, broadening the predominant focus on APOE {varepsilon}4 and identifying {varepsilon}2 as a potentially important but understudied contributor to altered neurovascular function.
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BibTeX
@misc{lucas2026apoe,
title = {{APOE Genotype and Fluid Biomarkers of Blood-Brain Barrier Integrity: A Systematic Review and Meta-Analysis}},
author = {W. Lucas and M. J. Murphy and N. Riddell},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.27.26364123},
url = {https://www.medrxiv.org/content/10.64898/2026.09.27.26364123v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - APOE Genotype and Fluid Biomarkers of Blood-Brain Barrier Integrity: A Systematic Review and Meta-Analysis
AU - W. Lucas
AU - M. J. Murphy
AU - N. Riddell
PY - 2026
DA - 2026/09/27
PB - medRxiv
DO - 10.64898/2026.09.27.26364123
UR - https://www.medrxiv.org/content/10.64898/2026.09.27.26364123v1
AB - 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 (sPDGFR{beta}). 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 sPDGFR{beta} 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 sPDGFR{beta}. Random-effects meta-analyses determined that APOE {varepsilon}2 carriage was associated with higher Q-Alb (g = 0.29, 95% CI 0.11 to 0.46). APOE {varepsilon}4 carriage was not associated with Q-Alb overall (g = .13, 95% CI -.17 to .43) or sPDGFR{beta} overall (g = .10, 95% CI -.21 to .40). Genotype-specific Q-Alb analyses suggested medium positive but non-significant effects among {varepsilon}4/{varepsilon}4 and {varepsilon}2/{varepsilon}4 carrier subgroups. For sPDGFR{beta}, 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 {varepsilon}4-associated alterations in Q-Alb and sPDGFR{beta} remained inconclusive, highlighting the need for further study across the spectrum of cognitive ageing and dementia. In contrast, APOE {varepsilon}2 carriage was associated with greater barrier dysfunction as indexed by Q-Alb, broadening the predominant focus on APOE {varepsilon}4 and identifying {varepsilon}2 as a potentially important but understudied contributor to altered neurovascular function.
ER -