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. 2025 Mar;21(3):e70040.
doi: 10.1002/alz.70040.

Exploratory analysis of the proteomic profile in plasma in adults with Down syndrome in the context of Alzheimer's disease

Olivia Wagemann  1   2 , Georg Nübling  1 , Francisco Jesús Martínez-Murcia  3 , Elisabeth Wlasich  1 , Sandra V Loosli  1   4 , Katja Sandkühler  1 , Anna Stockbauer  1   2 , Catharina Prix  1 , Sabrina Katzdobler  1   2 , Agnese Petrera  5 , Stefanie M Hauck  5 , Juan Fortea  6   7   8 , Rocío Romero-Zaliz  3   9 , Carmen Jiménez-Mesa  3 , Juan M Górriz Sáez  3 , Günter Höglinger  1   2   10 , Johannes Levin  1   2   10
Affiliations

Exploratory analysis of the proteomic profile in plasma in adults with Down syndrome in the context of Alzheimer's disease

Olivia Wagemann et al. Alzheimers Dement. 2025 Mar.

Abstract

Introduction: Adults with Down syndrome (DS) show increased risk for Alzheimer's disease (AD) due to the triplication of chromosome 21 encoding the amyloid precursor protein gene. Further, this triplication possibly contributes to dysregulation of the immune system, furthering AD pathophysiology.

Methods: Using Olink Explore 3072, we measured ∼3000 proteins in plasma from 73 adults with DS and 15 euploid, healthy controls (HC). Analyses for differentially expressed proteins (DEP) were carried out, and pathway and protein network enrichment using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING database was investigated. Within DS, the LASSO (least absolute shrinkage and selection operator) feature selection was applied.

Results: We identified 253 DEP between DS and HC and 142 DEP between symptomatic and asymptomatic DS. Several pathways regarding inflammatory and neurodevelopmental processes were dysregulated in both analyses. LASSO feature selection within DS returned 15 proteins as potential blood markers.

Discussion: This exploratory proteomic analysis found potential new blood biomarkers for diagnosing DS-AD in need of further investigation.

Highlights: Inflammatory pathways are dysregulated in symptomatic versus asymptomatic DS. NFL and GFAP are confirmed as powerful biomarkers in DS with clinical and/or cognitive decline. Further circulating proteins were identified as potential blood biomarkers for symptomatic DS.

Keywords: Alzheimer's disease; Down syndrome; biomarker; neuroinflammation; plasma.

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Conflict of interest statement

J.F. reports receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche and outside the submitted work as well as holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). G.H. serves as a consultant for Abbvie, Alzprotect, Amylyx, Aprinoia, Asceneuron, Bayer, Bial, Biogen, Biohaven, Epidarex, Ferrer, Kyowa Kirin, Lundbeck, Novartis, Retrotope, Roche, Sanofi, Servier, Takeda, Teva, UCB; received honoraria for scientific presentations from Abbvie, Bayer, Bial, Biogen, Bristol Myers Squibb, Esteve, Kyowa Kirin, Pfizer, Roche, Teva, UCB, Zambon; holds patents (US 10,918,628 B2; EP 17 787 904.6‐1109/3 525 788); received publication royalties from Academic Press, Kohlhammer, and Thieme. J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Esteve, 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” (PCT/EP2024/053388) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. J.M.G., S.M.H., S.K., C.J.M., G.N., S.V.L., F.J.M.M., A.P., C.P., R.R.Z., A.S., K.S., E.W., and O.W. report no conflict of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
(A) Volcano plot displaying the differences of DEP in adults with DS compared to HC. Accordingly, 211 DEP were found to be increased (e.g., CDH15, TFF1, and IL10RB) and 42 DEP showed reduced circulating protein levels in DS versus HC (e.g., OLFM4, PRG3, and CBLN4). (B) Distribution of all DEP (green) in relation to all proteins assessed (grey) and their respective chromosome revealed 11 DEP (37.9%) originating from chr21. (C) Top 20 enriched pathways from KEGG analysis in DS versus HC with the 10 most positive and negative normalized enrichment score (NES), respectively, and where the size of the dot refers to the number of proteins that have been put in for analysis and are annotated in the respective term. Here, cytokine–cytokine receptor interaction and CAMs turned up significantly enriched (arrows). (D) Significantly enriched terms from GO analysis for increased and suppressed pathways in DS compared to HC. DEP, differentially expressed proteins; DS, Down syndrome; GO, Gene Ontology; HC, healthy control; KEGG, Kyoto Encyclopedia of Genes and Genomes.
FIGURE 2
FIGURE 2
(A) Volcano plot displaying the differences of DEP in symptomatic versus asymptomatic adults with DS. Here, 133 DEP were found to with increased levels (e.g., GFAP, NEF, and IGFBP2) and 9 DEP showed decreased protein levels (e.g., CBLN4, CR2, and RET). (B) Distribution of all DEP (orange) in respect to all proteins assessed (grey) between symptomatic and asymptomatic DS regarding their respective chromosome with none of them originating from chr21. (C) Top 20 terms from KEGG Analysis, with 3 of them showing significant positive enrichment for symptomatic DS, and 1 negatively enriched pathway (arrows). (D) Significant terms from GO analysis for top enhanced or diminished pathways, respectively, in symptomatic versus asymptomatic DS. DEF, differentially expressed proteins; DS, Down syndrome; GFAP, glial fibrillary acidic protein; IGFBP2, insulin‐like growth factor binding protein‐2; KEGG, Kyoto Encyclopedia of Genes and Genomes; NEF, negative regulatory factor.
FIGURE 3
FIGURE 3
Top four clusters using the Markov–Cluster algorithm from PPI STRING network analysis of DEP between symptomatic and asymptomatic adults with DS with most significant enriched terms annotated in the legend suggesting differences in immune system signaling (cluster 1), the makeup of the extracellular matrix (cluster 2), enzymatic protein digestion (cluster 3), and Wnt signaling (cluster 4). Each node represents one DEP while each edge represents functional interaction between two DEP with the thickness of the edge increasing with the confidence of the proposed shared function. DEP, differentially expressed proteins; DS, Down syndrome; PPI, protein–protein interactions.
FIGURE 4
FIGURE 4
Box plots of individual NPX levels from symptomatic and asymptomatic adults with Down syndrome for all 15 proteins received from LASSO feature selection. LASSO, least absolute shrinkage and selection operator; NPX, normalized protein expression.
FIGURE 5
FIGURE 5
All nine proteins received from feature selection analysis with their corresponding AUC for diagnostic performance of differentiating between symptomatic and asymptomatic DS with corresponding ROC curves and an AUC over 0.75. AUC, area under the curve; DS, Down syndrome; ROC, receiver operating characteristics.
See this image and copyright information in PMC

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