# Reshaping ApoE4 and Alzheimer's Brains with ApoE2

> **NIH NIH R01** · UNIVERSITY OF KANSAS LAWRENCE · 2024 · $764,401

## Abstract

PROJECT SUMMARY
The research we propose in this application seeks to translate our recent understanding of the
neuroprotective mechanism associated with the human apolipoprotein E2 (ApoE2) genotype into a
therapeutic opportunity to prevent and treat Alzheimer's disease (AD). The overarching hypotheses
are that introduction of human ApoE2 protein into high-risk ApoE4 and AD brains positively alters the
course of brain aging or disease pathogenesis by bolstering brain resilience through enhanced
glycolytic metabolism, which subsequently improves glucose utilization, protein homeostasis, and
synaptic activity. In preparation, we have achieved three major milestones critical to the success
of this translational endeavor: (1) development of a method for the production of physiologically
relevant and human-compatible recombinant ApoE2 (rhApoE2) glycoprotein that possesses biological
functionality comparable to endogenous human ApoE2; (2) development of a noninvasive approach
for brain delivery of rhApoE2 glycoprotein via modulation of cadherin interactions on the blood-brain
barrier (BBB), which induces neuroprotective signaling in ApoE4 brains; and (3) development of novel
humanized knock-in mouse models that respectively target human sporadic (sAD) and familial AD
(fAD), which are expected to provide high predictive validity for translating bench successes to
bedside. The proposed studies will pursue three specific aims. Building on our initial success, the
objective of the first aim is to determine the therapeutically optimal regimen for delivery of rhApoE2
glycoprotein that will result in deposition of rhApoE2 throughout cortical and hippocampal regions and
upregulation of brain glycolytic metabolism without eliciting adverse reactions. The objective of the
second aim is to evaluate the therapeutic impact of rhApoE2 delivery, in combination with age and
sex, on brain changes associated with sAD in humanized mouse models that express physiological
levels of human ApoE3 or ApoE4 and human wild-type APP proteins. The third aim will be
investigated in humanized mouse models that express physiological levels of human ApoE3 or ApoE4
and human mutant APP proteins to evaluate the therapeutic impact of rhApoE2 delivery on brain
changes associated with fAD, and how the rhApoE2-mediated effects are modified by a combination
of age, sex, ApoE genotype, and disease status. Our overall goals for the proposed research are
to establish the plausibility of targeting brain metabolic resilience as a disease-modifying strategy and
generate proof of concept as to whether a rhApoE2-based protein therapy can potentially be
developed into an effective and safe intervention for AD.

## Key facts

- **NIH application ID:** 10765663
- **Project number:** 5R01AG071682-03
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** TERUNA J. SIAHAAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $764,401
- **Award type:** 5
- **Project period:** 2022-01-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765663

## Citation

> US National Institutes of Health, RePORTER application 10765663, Reshaping ApoE4 and Alzheimer's Brains with ApoE2 (5R01AG071682-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10765663. Licensed CC0.

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