1. CSF proteomics identifies early changes in autosomal dominant Alzheimer's disease.
- Author
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Shen Y, Timsina J, Heo G, Beric A, Ali M, Wang C, Yang C, Wang Y, Western D, Liu M, Gorijala P, Budde J, Do A, Liu H, Gordon B, Llibre-Guerra JJ, Joseph-Mathurin N, Perrin RJ, Maschi D, Wyss-Coray T, Pastor P, Renton AE, Surace EI, Johnson ECB, Levey AI, Alvarez I, Levin J, Ringman JM, Allegri RF, Seyfried N, Day GS, Wu Q, Fernández MV, Tarawneh R, McDade E, Morris JC, Bateman RJ, Goate A, Ibanez L, Sung YJ, and Cruchaga C
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Mutation, Aged, Machine Learning, Alzheimer Disease cerebrospinal fluid, Alzheimer Disease genetics, Alzheimer Disease pathology, Alzheimer Disease metabolism, Proteomics methods, Biomarkers cerebrospinal fluid
- Abstract
In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers., Competing Interests: Declaration of interests C.C. has received research support from GSK and EISAI. C.C. is a member of the advisory board of Circular Genomics and owns stocks in these companies. C.C. is on the advisory board of ADmit. J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Merck, and Roche; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6). He receives compensation for serving as chief medical officer for MODAG GmbH and is a beneficiary of the phantom share program of MODAG GmbH. E.M. reports research support received from NIA (U01AG059798), Anonymous Foundation, GHR, Alzheimer Association, Eli Lilly Eisai, and Hoffmann-La Roche and paid consulting for Eli Lilly, Alector, Alzamend, Sanofi, AstraZeneca, Hoffmann-La Roche, Grifols, and Merck., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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