# Anti-high molecular weight kininogen antibody for Alzheimer's disease diagnosis and therapy

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $412,290

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple pathologies, such as
proteinaceous brain inclusions and neuroinflammation. The vascular system is also recognized as a
factor in AD, yet there are few models to study the mechanism. We and others have found that the Aβ
peptide, a known driver of AD, can activate the plasma contact system, which can lead to blood clot
formation and inflammation via generation of bradykinin upon cleavage of high molecular weight
kininogen (HK). There are three main lines of evidence that the contact system is involved in AD
pathology: 1) Aβ activates factor XII (F12), which initiates the contact system; 2) AD patient plasma
has increased contact system activation compared to that of age-matched, non-demented individuals;
and 3) Knockdown of the contact system using an anti-F12 antisense oligonucleotide ameliorates AD
pathology in a mouse model. HK circulates in blood as a complex with other coagulation factors, and
it serves as a non-enzymatic co-factor for the activation of these proteins. Compared to other
components of the contact system, depletion of HK offers more robust protection from blood clotting
and inflammation due to its central role in both pathways.
We have generated antibodies that are specific for cleaved HK that could help identify AD patients
with contact system involvement. We also have developed antibodies that block HK cleavage, which
might be beneficial to patients as they might ameliorate some of the pathologies of AD. It is important
to note that people who lack a contact system are not prone to bleeding, and therefore, blocking this
system in AD patients would not risk intracerebral hemorrhage.
Despite decades of research, there are no effective treatments that slow or prevent AD. Progress in
treating AD requires a multidisciplinary approach. We hypothesize that blocking the contact system
could reduce vascular and inflammatory pathologies in AD patients. We propose to further develop
our anti-HK antibodies for AD patient diagnostic and therapeutic use.

## Key facts

- **NIH application ID:** 10875728
- **Project number:** 4R01AG069987-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Erin H. Norris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,290
- **Award type:** 4N
- **Project period:** 2020-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875728

## Citation

> US National Institutes of Health, RePORTER application 10875728, Anti-high molecular weight kininogen antibody for Alzheimer's disease diagnosis and therapy (4R01AG069987-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10875728. Licensed CC0.

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