TY - JOUR
T1 - Proteogenomic Evaluation of Cerebrospinal Fluid in Alzheimer's Disease
AU - Puerta, Raquel
AU - García-González, Pablo
AU - de Rojas, Itziar
AU - Olivé, Clàudia
AU - García-Gutiérrez, Fernando
AU - Sotolongo-Grau, Oscar
AU - Smets, Bart
AU - Emon, Asif
AU - Sung, Yun Ju
AU - Frikke-Schmidt, Ruth
AU - Marchant, Natalie L
AU - Lambert, Jean-Charles
AU - Valero, Sergi
AU - Marquié, Marta
AU - Ramirez, Alfredo
AU - Cruchaga, Carlos
AU - Fernández, Victoria
AU - Cano, Amanda
AU - Boada, Mercè
AU - Socorro, Alfredo Cabrera
AU - Ruiz, Agustin
N1 - © 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2024/12
Y1 - 2024/12
N2 - BACKGROUND: Alzheimer's disease (AD) is a complex disorder with a strong genetic component, yet many genetic risk factors remain unknown. Integrating genome-wide association studies (GWAS) and high-throughput proteomic platforms is a useful strategy to evaluate protein quantitative trait loci (pQTLs) and to detect candidate genes and pathways involved in AD. Due to the novelty of these techniques, the identification of reliable protein measures through a comprehensive quality control is mandatory.METHOD: We researched the cerebrospinal fluid (CSF) proteome using the SOMAscan 7k (7289 proteins), and the Olink Explore (2943 proteins) platform in the Ace Alzheimer Center Barcelona CSF Cohort. To assess reproducibility and reliability of proteomic measures, we analysed 1) intra-platform correlation of two independent SOMAscan assays using two aliquots of the same sample, and 2) inter-platform correlation between SOMAscan and Olink techniques. We also explored associations of highly reliable proteins with the AD Polygenic risk score (PRS) and the conversion to AD dementia. Additionally, we have performed an extensive pQTLs mapping of the SOMAscan platform and analysed pQTLs of significant proteins linked to disease progression.RESULT: Our results revealed 2469 proteins with high intra-platform correlation (rho≥0.5), selected as candidates for further analysis. Moreover, over 600 proteins demonstrated strong inter-platform correlation, reinforcing their robustness. Extending our analysis to the entire CSF cohort (n=1322), we identified 85 proteins (Padj.<0.05) associated with the AD-PRS. Additionally, 93 significant proteins were linked with conversion to AD dementia. Strikingly, these conversion-associated proteins exhibited 89 genome-wide significant pQTLs in the genome, with more than 47% of the genetic signals localized within the APOE-rs429358 locus.CONCLUSION: Our findings emphasize the importance of reliability assessment of highly multiplexed proteomic panels. Using robust measures, we identified significant proteins related to AD genetic risk and disease progression. These insights deepen the AD pathogenesis understanding, expand future research and therapeutic interventions.
AB - BACKGROUND: Alzheimer's disease (AD) is a complex disorder with a strong genetic component, yet many genetic risk factors remain unknown. Integrating genome-wide association studies (GWAS) and high-throughput proteomic platforms is a useful strategy to evaluate protein quantitative trait loci (pQTLs) and to detect candidate genes and pathways involved in AD. Due to the novelty of these techniques, the identification of reliable protein measures through a comprehensive quality control is mandatory.METHOD: We researched the cerebrospinal fluid (CSF) proteome using the SOMAscan 7k (7289 proteins), and the Olink Explore (2943 proteins) platform in the Ace Alzheimer Center Barcelona CSF Cohort. To assess reproducibility and reliability of proteomic measures, we analysed 1) intra-platform correlation of two independent SOMAscan assays using two aliquots of the same sample, and 2) inter-platform correlation between SOMAscan and Olink techniques. We also explored associations of highly reliable proteins with the AD Polygenic risk score (PRS) and the conversion to AD dementia. Additionally, we have performed an extensive pQTLs mapping of the SOMAscan platform and analysed pQTLs of significant proteins linked to disease progression.RESULT: Our results revealed 2469 proteins with high intra-platform correlation (rho≥0.5), selected as candidates for further analysis. Moreover, over 600 proteins demonstrated strong inter-platform correlation, reinforcing their robustness. Extending our analysis to the entire CSF cohort (n=1322), we identified 85 proteins (Padj.<0.05) associated with the AD-PRS. Additionally, 93 significant proteins were linked with conversion to AD dementia. Strikingly, these conversion-associated proteins exhibited 89 genome-wide significant pQTLs in the genome, with more than 47% of the genetic signals localized within the APOE-rs429358 locus.CONCLUSION: Our findings emphasize the importance of reliability assessment of highly multiplexed proteomic panels. Using robust measures, we identified significant proteins related to AD genetic risk and disease progression. These insights deepen the AD pathogenesis understanding, expand future research and therapeutic interventions.
KW - Humans
KW - Alzheimer Disease/genetics
KW - Genome-Wide Association Study
KW - Biomarkers/cerebrospinal fluid
KW - Female
KW - Male
KW - Quantitative Trait Loci
KW - Proteomics
KW - Aged
KW - Reproducibility of Results
KW - Cohort Studies
U2 - 10.1002/alz.086066
DO - 10.1002/alz.086066
M3 - Journal article
C2 - 39786192
SN - 1552-5260
VL - 20 Suppl 2
SP - e086066
JO - Alzheimer's & dementia : the journal of the Alzheimer's Association
JF - Alzheimer's & dementia : the journal of the Alzheimer's Association
ER -