A targeted association study of blood-brain barrier gene SNPs and brain atrophy

Document Type

Journal Article

Publication Title

Journal of Alzheimer's Disease


IOS Press


School of Medical and Health Sciences / Centre for Precision Health




Vacher, M., Porter, T., Milicic, L., Bourgeat, P., Dore, V., Villemagne, V. L., . . . Doecke, J. D. (2022). A targeted association study of blood-brain barrier gene SNPs and brain atrophy. Journal of Alzheimer's Disease, 86(4), 1817-1829. https://doi.org/10.3233/JAD-210644


Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens. Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP). Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change. Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOEɛ4 allele and were significant post correction for multiple comparisons. Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation.



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