Associations Between TREML2 Gene Variants and Alzheimer’s Disease: Biomarkers, Neuroimage, and Cognition

Article type: Research Article

Authors: Li, Jie-Qiong^{a; *; 1} | Zhong, Xiao-Ling^{b; 1} | Song, Jing-Hui^a | Chi, Song^a | Xie, An-Mu^a | Tan, Lan^c | Yu, Jin-Tai ^d | for the Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] Department of Neurology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China | [b] Department of Neurology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao, China | [c] Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China | [d] Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence: [*] Correspondence to: Jie-Qiong Li, MD, PhD, Department of Neurology, the Affiliated Hospital of Qingdao University, Qingdao University, No. 16 Jiangsu Road, Qingdao, China. Tel.: +0086 0532 82913052; E-mail: [email protected].

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

Note: [2] Data used in preparation of this paper 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 the analysis or in the writing of this paper. 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: Background: Recent genetic research identified a protective factor against late-onset Alzheimer’s disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. Objective: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer’s Disease Neuroimaging Initiative database (ADNI). Methods: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. Results: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Conclusion:Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.

Keywords: Alzheimer’s disease, cognition, gene, single nucleotide polymorphisms, TREML2

DOI: 10.3233/JAD-230936

Journal: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1555-1563, 2023