Methionine Sulfoxide Reductase-B3 Risk Allele Implicated in Alzheimer’s Disease Associates with Increased Odds for Brain Infarcts

Article type: Research Article

Authors: Conner, Sarah C.^{a; b} | Benayoun, Laurent^c | Himali, Jayandra J.^{a; b; e} | Adams, Stephanie L.^c | Yang, Qiong^{a; b} | DeCarli, Charles^d | Blusztajn, Jan K.^c | Beiser, Alexa^{a; b; e} | Seshadri, Sudha^{a; e} | Delalle, Ivana^{c; e; *}

Affiliations: [a] Framingham Heart Study, Boston University School of Public Health, Boston, MA, USA | [b] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [c] Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA | [d] Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA | [e] Department of Neurology, Boston University School of Medicine, Boston, MA, USA

Correspondence: [*] Correspondence to: Ivana Delalle, Department of Pathology and Laboratory Medicine, 72 East Concord Street, Boston University School of Medicine, Boston, MA 02118, USA. Tel.: +1 617 414 7014; Fax: +1 617 414 7040; E-mail: [email protected].

Abstract: Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer’s disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502, G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998–2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoprotein ɛ4 allele (APOE4), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4.

Keywords: Framingham Heart Study, hippocampus, MSRB3 , vascular pathology

DOI: 10.3233/JAD-180977

Journal: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 357-365, 2019