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.
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2022-12
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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 survival in absence of AD-progression 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.Type
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Li, Huiyue, Hongliang Liu, Michael W Lutz, Sheng Luo and undefined Alzheimer’s Disease Neuroimaging Initiative (2022). 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. Journal of Alzheimer's disease : JAD. pp. 1–11. 10.3233/jad-220680 Retrieved from https://hdl.handle.net/10161/26404.
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Scholars@Duke
Michael William Lutz
Developing and using computational biology methods to understand the genetic basis of disease with a focus on Alzheimer’s Disease. Recent work has focused on identification and validation of clinically-relevant biomarkers for Alzheimer’s disease and Alzheimer’s disease with Lewy bodies.
Sheng Luo
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