# Cerebral amyloid angiopathy: Role of ApoE, innate immunity, and meningeal lymphatics

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2022 · $627,998

## Abstract

Abstract: Project 2 will investigate the interplay of APOE genotype, innate immunity, and meningeal
lymphatics on cerebral amyloid angiopathy (CAA) and the translational implications of modifying lymphatic
function on passive immunotherapy of CAA. CAA occurs in ~90% of individuals who develop Alzheimer’s
disease (AD) and can occur independently of AD. The pathological hallmarks of CAA are deposition of amyloid
composed in the majority of cases of amyloid-β (Aβ) along small arteriole vessel walls of the cerebral
vasculature and leptomeninges. CAA leads to loss of vascular smooth muscle cells, impaired vasoreactivity,
hemorrhages, and ischemia resulting in cognitive impairment and transient ischemic episodes. CAA is also
linked with edema and microhemorrhages that are common side effects observed with several anti-Aβ
antibodies known as amyloid-related imaging abnormalities (ARIA). The mechanisms underlying the
development of CAA are not well understood, but prior studies indicate that APOE genotype, perivascular fluid
flux, and innate immune cells can all influence CAA pathology. Like AD, APOE4 increases the risk of
developing CAA. Recently, we demonstrated that anti-apoE antibodies that target a form of apoE that co-
deposits with vascular amyloid reduced CAA and improved vascular function. In the brain parenchyma, apoE is
predominantly expressed by astrocytes and reactive microglia. Vascular-associated cells, such as perivascular
macrophages (PVMs), pericytes, and the recently described fibroblast-like vascular leptomeningeal cells
(VLMCs) are also reported to express apoE. ApoE produced by different cell types differ in their lipidation state
and post-translational modifications which could suggest a cell-specific role for apoE in CAA or subsequent
vascular dysfunction and inflammation. Recent studies by the Kipnis lab have shown important contributions of
the meningeal lymphatic system to Aβ deposition in parenchymal and leptomeningeal plaques. Impaired
clearance of Aβ from perivascular spaces may also contribute to the formation of CAA, although the role of the
meningeal immune system and the meningeal lymphatics in CAA formation and pathogenesis is unexplored.
We hypothesize that 1) apoE plays a multifaceted role in CAA formation by influencing perivascular Aβ
seeding and clearance in part via the meningeal lymphatic system and perivascular immune cells, 2)
the meningeal lymphatic system plays a key role in CAA formation; and 3) augmenting the meningeal
lymphatic system will increase the efficacy of anti-apoE immunotherapy reduction of CAA. We propose
these Aims: Aim 1: To determine effect of cell-type specific apoE expression on CAA and meningeal lymphatic
function. Aim 2: To determine the role of meningeal lymphatics on CAA pathology and associated
inflammation and vascular dysfunction. Aim 3: To determine the effect of lymphatic function on the efficacy of
anti-apoE antibody treatment on CAA and vascular dysfunction. Project 2 will collab...

## Key facts

- **NIH application ID:** 10492258
- **Project number:** 1P01AG078106-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DAVID M. HOLTZMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $627,998
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492258

## Citation

> US National Institutes of Health, RePORTER application 10492258, Cerebral amyloid angiopathy: Role of ApoE, innate immunity, and meningeal lymphatics (1P01AG078106-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10492258. Licensed CC0.

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