Effect of EPHA1 Genetic Variation on Cerebrospinal Fluid and Neuroimaging Biomarkers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts

Article type: Research Article

Authors: Wang, Hui-Fu^a | Tan, Lan^{a; b; c; d; *} | Hao, Xiao-Ke^e | Jiang, Teng^a | Tan, Meng-Shan^c | Liu, Ying^d | Zhang, Dao-Qiang^e | Yu, Jin-Tai^{a; b; f; *} | for the Alzheimer's Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China | [b] Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China | [c] Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China | [d] Department of Neurology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, China | [e] Department of Computer Science and Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China | [f] Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA

Correspondence: [*] Correspondence to: Dr Lan Tan or Jin-Tai Yu, Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province 266071, China. E-mails: dr.tanlan@163.com (L. Tan); yu-jintai@163.com (J.T. Yu).

Note: [1] Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Ephrin type-A receptor 1 (EPHA1) (11771145) was documented to be one of the most strongly associated locus with Alzheimer's disease (AD) in a recent meta-analysis of five genome wide association studies. However, its contribution to the pathogenesis of AD remains unclear to date. Here, we addressed the role of EPHA1 in AD by investigating the influence of EPHA1 on cerebrospinal fluid and neuroimaging biomarkers in three clinical stages from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We did not detect significant association of EPHA1 with amyloid-β deposition or tau protein. However, the A-allele in the mild cognitive impairment group remarkably prevented hippocampal atrophy (partial correlation coefficient 2.812, 95% CI 0.651 to 4.973) at two-year follow-up. Additionally, AD subjects with the A-allele displayed less atrophy and greater cerebral metabolic rate for glucose (CMRgl) in the right lateral occipitotemporal gyrus (volume: partial correlation coefficient 540.10, 95% CI 247.26 to 832.95; CMRgl: partial correlation coefficient 0.056, 95% CI 0.024 to 0.087) and inferior temporal gyrus (volume: partial correlation coefficient 327.98, 95% CI 11.65 to 644.31; CMRgl: partial correlation coefficient 0.055, 95% CI 0.019 to 0.091) at baseline. This study suggests EPHA1 (rs11771145) interferes with the pathological alteration of the hippocampus and the lateral occipitotemporal and inferior temporal gyri throughout the AD process, leading to a lower risk of AD. However, the limited sample size and follow-up as well as the diversity across ethnicities precluded explanation of these findings.

Keywords: Alzheimer's disease, Alzheimer's Disease Neuroimaging Initiative (ADNI), biomarker, cerebrospinal fluid, Ephrin type-A receptor 1 (EPHA1), neuroimaging

DOI: 10.3233/JAD-141488

Journal: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 115-123, 2015