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. 2025 Aug;21(8):e70579.
doi: 10.1002/alz.70579.

Plasma proteomic analysis identifies proteins and pathways related to Alzheimer's risk

Yen-Ning Huang  1   2 , Shiwei Liu  1   2 , Tamina Park  1   2 , Soumilee Chaudhuri  1   2   3 , Lindsey A Kuchenbecker  4   5 , Minerva M Carrasquillo  4   5 , Nilüfer Ertekin-Taner  4 , Paula J Bice  1   2 , Henrik Zetterberg  6   7   8   9   10   11 , Kaj Blennow  6   7   12   13 , Kristen Russ  3   14 , Jeffrey L Dage  2   3   14   15 , Kelly N H Nudelman  2   15 , Carlos Cruchaga  16   17 , Jared R Brosch  1   2   14 , Martin R Farlow  1   2   18 , David G Clark  1   2   14 , Sunu Mathew  1   2 , Frederick Unverzagt  1   2   18 , Sujuan Gao  1   2   19 , Sophia Wang  1   2   18 , Liana G Apostolova  1   2   14 , Donna M Wilcock  3   14 , Tatiana Foroud  15 , Shannon L Risacher  1   2 , Andrew J Saykin  1   2   15 , Kwangsik Nho  1   2   20
Affiliations

Plasma proteomic analysis identifies proteins and pathways related to Alzheimer's risk

Yen-Ning Huang et al. Alzheimers Dement. 2025 Aug.

Abstract

Introduction: We investigated associations of plasma proteins with blood-based amyloid/tau/neurodegeneration/inflammation (A/T/N/I) biomarkers for Alzheimer's disease (AD).

Methods: Plasma proteomics and clinical data from the Indiana AD Research Center (N = 498) were used. Association analysis of plasma proteins with blood A/T/N/I biomarkers as well as diagnosis was performed, followed by replication in an independent cohort (N = 323), network analysis, pathway enrichment, and machine learning classification to identify proteins and pathways related to AD risk.

Results: We identified 35 proteins associated with AD, 20 of which were replicated in the independent cohort. We identified 150, 448, and 219 proteins associated with T/N/I biomarkers, respectively, revealing biomarker-specific pathways. Network analysis identified two modules associated with T/N/I biomarkers, preserved in cerebrospinal fluid (CSF), and their enriched pathways. The classification model of proteins effectively differentiated AD (area under the curve [AUC] = 0.930).

Conclusion: Our findings suggest dysregulated plasma proteins and pathways in AD, enhancing our understanding of molecular mechanisms and diagnostic strategies for AD.

Highlights: Plasma proteins were identified as being associated with Alzheimer's disease (AD) and plasma biomarkers. The identified proteins were replicated in both plasma and cerebrospinal fluid (CSF) proteomics. The identified proteins were associated with AD biomarker-specific pathways. The identified proteins improved the performance of the AD classification. Protein network analysis identified network modules and their enriched pathways.

Keywords: Alzheimer's disease; SomaScan; amyloid; biomarker; inflammation; machine learning; network analysis; neurodegeneration; plasma; proteomics; tau.

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Conflict of interest statement

A.S. has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and participated in Scientific Advisory Boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc) and an Observational Study Monitoring Board (MESA, NIH NHLBI), as well as several other NIA External Advisory Committees. He also serves as Editor‐in‐Chief of Brain Imaging and Behavior, a Springer‐Nature Journal. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). C.C. has received research support from GSK and EISAI. C.C. is a member of the scientific advisory board of Circular Genomics and owns stocks. C.C. is a member of the scientific advisory board of ADmit. Y.H, S.L, T.P, S.C, L.A.K, M.M.C, N.E.T, P.J.B, K.B, K.R, J.L.D, K.N.H.N, J.R.B, M.R.F, D.G.C, S.M, F.U, S.G, S.W, L.G.A, D.M.W, T.F, S.L.R, K.N. have no competing interests in this study. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Workflow diagram of the study. A/T/N/I, amyloid/tau/neurodegeneration/inflammation; ADNI, Alzheimer's Disease Neuroimaging Initiative; CSF, cerebrospinal fluid; FCA3DS, Florida African American Alzheimer's Disease Studies; IADRC, Indiana Alzheimer's Disease Research Center.
FIGURE 2
FIGURE 2
Volcano plot for plasma proteins significantly associated with AD. The 11 red dots represent proteins with significantly higher abundance (FDR‐adjusted p < 0.05) in the AD group compared to the CN group, while the 26 blue dots represent proteins with significantly lower abundance in the AD group. The five most significantly upregulated and downregulated protein names are given. Note: Two aptamers correspond to the same protein, NPTXR. AD, Alzheimer's disease; CN, cognitively normal older adults; FDR, false discovery rate; NPTXR, neuronal pentraxin receptor.
FIGURE 3
FIGURE 3
Volcano plot and Venn diagram of plasma proteins significantly associated with plasma AD biomarkers, highlighting the top five proteins with the most significant positive and negative associations with plasma T/N/I biomarkers (P‐tau181, NfL, and GFAP). (A) Volcano plot of plasma proteins significantly associated with the plasma ‘T’ biomarker. (B) Volcano plot of plasma proteins significantly associated with the plasma ‘N’ biomarker. (C) Volcano plot of plasma proteins significantly associated with the plasma ‘I’ biomarker. (D) Venn diagram shows the overlapping numbers of plasma proteins significantly associated with plasma AD biomarkers. AD, Alzheimer's disease; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; T/N/I, tau/neurodegeneration/inflammation.
FIGURE 4
FIGURE 4
Comparison of T‐value and FDR‐adjusted p‐values of significant WGCNA modules across the plasma A/T/N/I biomarkers. Note: * indicates 0.01 ≤ FDR‐adjusted p‐value < 0.05; ** indicates 0.001 ≤ FDR‐adjusted p‐value < 0.01; *** indicates FDR‐adjusted p‐value < 0.001. A/T/N/I, amyloid/tau/neurodegeneration/inflammation; FDR, false discovery rate; WGCNA, weighted gene co‐expression network analysis.
FIGURE 5
FIGURE 5
(A) The pathway enrichment network includes 70 proteins within module M7 with their 10 significant biological pathways, which were ranked by FDR‐adjusted p‐value. (B) The dot plot for enriched GO terms. The pathways are represented on the y‐axis, with their enrichment levels indicated along the x‐axis by the gene ratio. Pathways with higher gene ratios are positioned further to the right, reflecting a stronger relative contribution of proteins to those pathways. The size of the dots represents the number of proteins in the significant protein list associated with the GO term, and the color of the dots represents the FDR‐adjusted p‐value. FDR, false discovery rate; GO, gene ontology.
FIGURE 6
FIGURE 6
Machine learning classification of AD using the elastic net algorithm. (A) ROC and the AUC of Model 1 (age + sex + APOE ε4 carrier status) were calculated, yielding a mean value of 0.625 across five independent runs of 3‐fold cross‐validation. (B) ROC and the AUC of Model 2 (age + sex + APOE ε4 carrier status + plasma A/T/N/I biomarkers) were calculated, yielding a mean of 0.904 across five independent runs of 3‐fold cross‐validation. (C) ROC and the AUC of Model 3 (age + sex + APOE ε4 carrier status + plasma A/T/N/I biomarkers + 20 plasma proteins (22 aptamers)) were calculated, yielding a mean of 0.930 across five independent runs of 3‐fold cross‐validation. The blue curve represents the mean AUC from 3‐fold cross‐validation, and the background curves indicate the ROC curve for each cross‐validation fold, while the shaded area indicates ± 1 standard deviation around the mean ROC curve. A/T/N/I, amyloid/tau/neurodegeneration/inflammation; APOE, apolipoprotein E; AUC, area under the curve; ROC, receiver operating characteristic.
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