Biochemistry and Pharmacology - Research Publications

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Author: Masters, Colin × End date: 2021 × Start date: 2020 × Type: Journal Article ×

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    Extracellular vesicular lipids as biomarkers for the diagnosis of Alzheimer’s disease
    Su, H ; Rustam, YH ; Masters, CL ; Makalic, E ; McLean, C ; Hill, AF ; Barnham, KJ ; Reid, GE ; Vella, LJ (Wiley, 2021-12-31)
    An increasing number of studies have revealed that dysregulated lipid homeostasis is associated with the pathological processes that lead to Alzheimer’s disease (AD). If changes in key lipid species could be detected in the periphery, it would advance our understanding of the disease and facilitate biomarker discovery. Global lipidomic profiling of sera/blood however has proved challenging with limited disease or tissue specificity. Small extracellular vesicles (EV) in the central nervous system, can pass the blood-brain barrier and enter the periphery, carrying a subset of lipids that could reflect lipid homeostasis in brain. This makes EVs uniquely suited for peripheral biomarker exploration.
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    Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture
    Zhang, Q ; Sidorenko, J ; Couvy-Duchesne, B ; Marioni, RE ; Wright, MJ ; Goate, AM ; Marcora, E ; Huang, K-L ; Porter, T ; Laws, SM ; Sachdev, PS ; Mather, KA ; Armstrong, NJ ; Thalamuthu, A ; Brodaty, H ; Yengo, L ; Yang, J ; Wray, NR ; McRae, AF ; Visscher, PM (NATURE RESEARCH, 2020-09-23)
    Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer’s disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.