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Background <p>Cardiometabolic and inflammatory pathways may play important roles in Alzheimer’s disease (AD) pathogenesis contributing to neuronal dysfunction even in the absence of cognitive symptoms. Our objective is to characterize proteomic signatures of these pathways in AD.</p> Methods <p>We perform CSF and plasma-targeted proteomics using Olink’s highly sensitive proximity extension assay from 354 participants, of which 4.2% had preclinical AD, and 19.5% had prodromal AD. Using data-driven bioinformatic pipeline, we describe proteomic signatures based on various AD traits.</p> Results <p>The 276 measured proteins cluster into five modules that are associated with AD biomarkers and disease traits. We identify an AD signature in the CSF characterized by elevated levels of Hepatocyte Growth Factor (<i>HGF</i>), Intercellular and Vascular Cell Adhesion Molecules 1 (ICAM-1, <i>VCAM-1</i>), Neuropilin 1 and 2 (<i>NRP-1</i>, <i>NRP-2</i>), Scavenger Receptor Class B Member 2 (<i>SCARB2</i>), and Plasminogen Activator Urokinase (<i>PLAU</i>) that was detectable even in preclinical AD. This signature also predicts clinical disease progression. Independent validation (n = 75) suggests that CSF adhesion molecules showed significant positive correlation with CSF Aβ−42: (R<sup>2</sup> ranged: 0.05-0.44) and pTau (R<sup>2</sup> ranged: 0.15-0.70).</p> Conclusions <p>Our results identify a signature centered around CSF vascular adhesion proteins that associates with AD pathology and disease progression, with elevation detectable even in the preclinical stage, warranting further mechanistic investigation.</p>

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Adhesion molecules provide an endothelial protein signature in preclinical and clinical Alzheimer’s disease and predict clinical progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Ihab M. Hajjar,
  • Reem Neal,
  • Namrata Singh,
  • Zhiyi Yang,
  • Malik Obideen,
  • Amil M. Shah,
  • Eric B. Dammer

摘要

Background

Cardiometabolic and inflammatory pathways may play important roles in Alzheimer’s disease (AD) pathogenesis contributing to neuronal dysfunction even in the absence of cognitive symptoms. Our objective is to characterize proteomic signatures of these pathways in AD.

Methods

We perform CSF and plasma-targeted proteomics using Olink’s highly sensitive proximity extension assay from 354 participants, of which 4.2% had preclinical AD, and 19.5% had prodromal AD. Using data-driven bioinformatic pipeline, we describe proteomic signatures based on various AD traits.

Results

The 276 measured proteins cluster into five modules that are associated with AD biomarkers and disease traits. We identify an AD signature in the CSF characterized by elevated levels of Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecules 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2 (SCARB2), and Plasminogen Activator Urokinase (PLAU) that was detectable even in preclinical AD. This signature also predicts clinical disease progression. Independent validation (n = 75) suggests that CSF adhesion molecules showed significant positive correlation with CSF Aβ−42: (R2 ranged: 0.05-0.44) and pTau (R2 ranged: 0.15-0.70).

Conclusions

Our results identify a signature centered around CSF vascular adhesion proteins that associates with AD pathology and disease progression, with elevation detectable even in the preclinical stage, warranting further mechanistic investigation.