TY - JOUR
T1 - Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease
AU - Frick, Elisabet A.
AU - Emilsson, Valur
AU - Jonmundsson, Thorarinn
AU - Steindorsdottir, Anna E.
AU - Johnson, Erik C.B.
AU - Puerta, Raquel
AU - Dammer, Eric B.
AU - Shantaraman, Anantharaman
AU - Cano, Amanda
AU - Boada, Mercè
AU - Valero, Sergi
AU - García-González, Pablo
AU - Gudmundsson, Elias F.
AU - Gudjonsson, Alexander
AU - Pitts, Rebecca
AU - Qiu, Xiazi
AU - Finkel, Nancy
AU - Loureiro, Joseph J.
AU - Orth, Anthony P.
AU - Seyfried, Nicholas T.
AU - Levey, Allan I.
AU - Ruiz, Agustin
AU - Aspelund, Thor
AU - Jennings, Lori L.
AU - Launer, Lenore J.
AU - Gudmundsdottir, Valborg
AU - Gudnason, Vilmundur
N1 - Publisher Copyright:
© The Author(s) 2024. corrected publication 2024.
PY - 2024/10
Y1 - 2024/10
N2 - A deeper understanding of the molecular processes underlying late-onset Alzheimer’s disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status.
AB - A deeper understanding of the molecular processes underlying late-onset Alzheimer’s disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status.
UR - http://www.scopus.com/inward/record.url?scp=85201620727&partnerID=8YFLogxK
U2 - 10.1038/s43587-024-00693-1
DO - 10.1038/s43587-024-00693-1
M3 - Article
C2 - 39169269
AN - SCOPUS:85201620727
SN - 2662-8465
VL - 4
SP - 1446
EP - 1464
JO - Nature Aging
JF - Nature Aging
IS - 10
ER -