# Studying Pathogenic Mechanism of Hereditary Cerebral Amyloid Angiopathy

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2022 · $1

## Abstract

Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and a damaged cerebral
vasculature. Moreover, the majority of patients with dementia present with both AD and vascular pathologies.
Circulatory deficiencies could therefore play an important role in this disease. Cerebral amyloid angiopathy
(CAA), where Aβ deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in AD
and is observed in more than 80% of AD patients. Post-mortem pathological examination of patients' brains
with CAA shows perivascular microhemorrhage, microinfarcts, and capillary occlusion. However, the molecular
mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. In addition, a
definitive diagnosis of CAA requires autopsy as there is no clear biomarker for CAA.
There are rare familiar forms of CAA, called hereditary cerebral amyloid angiopathy (HCAA), in which patients
display exaggerated CAA pathology and a severe clinical course of strokes as well as suffering from early
onset neurological dysfunction, dementia, and ultimately death. The majority of HCAA occurrences coincide
with mutations within the gene for the β-amyloid precursor protein (APP). While most APP mutations elevate
total Aβ production or promote formation of the more toxic Aβ42, a subset of mutations related to HCAA
causes an increase in vascular deposits of Aβ. Since patients afflicted by HCAA mutations have severe
cerebrovascular deficits along with massive CAA, HCAA is an ideal disease to examine the pathogenic
mechanisms of CAA.
Increasing evidence suggests that fibrinogen, a major component of blood clots, contributes heavily to the
cerebrovascular risk in AD. Fibrinogen binds to Aβ with high affinity, and this interaction increases the
incidence of abnormal fibrin clots, CAA, inflammation, and cerebrovascular damage. Our preliminary results
indicate that HCAA mutations highly increase Aβ’s binding affinity for fibrinogen and induce more severely
altered fibrin clot structure than wild-type (WT) Aβ. Based on these findings, we hypothesize that HCAA
mutations increase Aβ’s binding affinity for fibrinogen, which subsequently induces more severely altered fibrin
clotting, increases vascular fibrin and Aβ deposition, and exacerbates inflammation and cerebrovascular
damage. By investigating our hypothesis in a mouse model of HCAA, as well as antemortem CSF and
postmortem brain tissue of HCAA patients, we aim to understand the molecular mechanism underlying
increased CAA and cerebrovascular abnormalities in HCAA. If our proposed experiments are successful, the
results will help us to better understand the pathogenic mechanism underlying the vascular contribution of CAA
in both AD and HCAA patients. In addition, our research will provide a novel CSF biomarker for CAA.
Furthermore, these findings may accelerate the discovery of tractable therapeutic methods for vascular
pathology in AD.

## Key facts

- **NIH application ID:** 10817441
- **Project number:** 7R01NS104386-07
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Hyung Jin Ahn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1
- **Award type:** 7
- **Project period:** 2018-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817441

## Citation

> US National Institutes of Health, RePORTER application 10817441, Studying Pathogenic Mechanism of Hereditary Cerebral Amyloid Angiopathy (7R01NS104386-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10817441. Licensed CC0.

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