A Targeted Association Study of Blood-Brain Barrier Gene SNPs and Brain Atrophy

Article type: Research Article

Authors: Vacher, Michael^{a; b; c; *} | Porter, Tenielle^{b; c; d} | Milicic, Lidija^{b; c} | Bourgeat, Pierrick^e | Dore, Vincent^e | Villemagne, Victor L^{f; g} | Laws, Simon M.^{b; c; d; **} | Doecke, James D.^{e; **}

Affiliations: [a] CSIRO Health and Biosecurity, Australian e-Health Research Centre, Floreat, WA, Australia | [b] Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia | [c] Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia | [d] School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia | [e] CSIRO Health and Biosecurity, Australian e-Health Research Centre, Herston, Qld, Australia | [f] Department of Molecular Imaging & Therapy and Centre for PET, Austin Health, Heidelberg, Vic, Australia | [g] Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: [*] Correspondence to: Michael Vacher, CSIRO Health and Biosecurity, Australian e-Health Research Centre, Floreat 6014, WA, Australia. E-mail: michael.vacher@csiro.au.

Abstract: 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.

Keywords: Alzheimer’s disease, blood-brain barrier, brain atrophy, linear mixed model, MRI, single nucleotide polymorphisms

DOI: 10.3233/JAD-210644

Journal: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1817-1829, 2022