Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer’s Disease

Article type: Research Article

Authors: Li, Huiyue^a | Liu, Hongliang^{b; c} | Lutz, Michael W.^d | Luo, Sheng^{a; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA | [b] Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA | [c] Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA | [d] Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, USA

Correspondence: [*] Correspondence to: Sheng Luo, Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC. Durham, NC 77030, USA. Tel.: +1 919 668 8038; Fax: +1 919 668 8038; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://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: Background:Alzheimer’s disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear. Objective:We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression. Methods:We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from the Alzheimer’s Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer’s Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression. Results:We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤0.8. Based on the linkage disequilibrium clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year progression to AD from MCI significantly increased the predictive accuracy. Conclusion:Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway.

Keywords: Mild cognitive impairment, neurotrophins, single nucleotide polymorphism, survival analysis

DOI: 10.3233/JAD-220680

Journal: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 977-987, 2023