# Contact System and Alzheimer's Disease: Mechanism and Therapeutic Potential

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $844,508

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is a complex, multifactorial disease that leads to profound
neurodegeneration, cognitive decline, and eventually death. There is strong evidence that the
Alzheimer's beta-amyloid peptide (Aβ) is an important driver of the disease. However, the
mechanisms by which Aβ is toxic are not defined.
There is increasing evidence that inflammation and vascular abnormalities contribute to AD
pathology. One pathway that links these two processes is the plasma contact system. We have
found that this system can be initiated by Aβ and is activated in AD plasma from human patients
and mouse models. Furthermore, inhibition of the contact system in AD mice improves their
pathology and cognition.
We propose to further define how the contact system and its components, specifically high
molecular weight kininogen (HK) and coagulation factor XII (FXII), contribute to AD
pathophysiology. We have found that Aβ protofibrils are the most effective Aβ species to
activate the contact system. Aβ protofibrils are also the main target of lecanemab, the promising
new FDA-approved antibody therapy for AD patients. We will investigate how lecanemab might
interfere with the contact system to generate its beneficial effects in humans and determine if
both lecanemab and a contact system inhibitor could have a synergistic effect on AD pathology.
We will also study the structural interaction between Aβ protofibrils, HK, and FXII to determine
mechanistically how Aβ causes contact system dysfunction in AD. Finally, we will explore the
potential of an anti-HK antibody as a new therapeutic avenue for AD.

## Key facts

- **NIH application ID:** 10802820
- **Project number:** 2R01NS102721-06A1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Erin H. Norris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $844,508
- **Award type:** 2
- **Project period:** 2018-04-15 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802820

## Citation

> US National Institutes of Health, RePORTER application 10802820, Contact System and Alzheimer's Disease: Mechanism and Therapeutic Potential (2R01NS102721-06A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10802820. Licensed CC0.

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