ABCA7 Genotypes Confer Alzheimer’s Disease Risk by Modulating Amyloid-β Pathology

Article type: Research Article

Authors: Zhao, Qing-Fei^{a; 1} | Wan, Yu^{a; 1} | Wang, Hui-Fu^b | Sun, Fu-Rong^a | Hao, Xiao-Ke^c | Tan, Meng-Shan^a | Tan, Chen-Chen^a | Zhang, Dao-Qiang^c | Tan, Lan^{a; b; *} | Yu, Jin-Tai^{a; b; *} | Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China | [b] Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China | [c] Department of Computer Science and Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China

Correspondence: [*] Correspondence to: Dr. Lan Tan, MD, PhD, Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province 266071, China. Tel./Fax: +86 532 8890 5659; E-mail: [email protected] and Dr. Jin-Tai Yu, MD, PhD, Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China. Tel./Fax: +86 532 8890 5659; E-mails: [email protected] or [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://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: ABCA7 gene has been identified as a strong genetic locus for Alzheimer’s disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1 - 42, T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism.

Keywords: ABCA7, Aβ pathogenesis, Alzheimer’s disease, Alzheimer’s disease neuroimaging initiative

DOI: 10.3233/JAD-151005

Journal: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 693-703, 2016