# The Role of Apolipoprotein E4 in Neuronal Insulin Resistance and Alzheimer's Disease

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $33,570

## Abstract

Insulin Sensitization by Shc Inhibition as a Novel Alzheimer's Disease Therapeutic Strategy.
Apolipoprotein E4 is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD) and a potential
pathomechanism is via neuronal insulin resistance (NIR). I will investigate this pathomechanism, specifically
the kinetics and effect of binding of ApoE4 to insulin receptor (IR), and I will test if insulin-sensitizing Shc
blockers can rescue parameters of insulin signaling, downstream mitochondrial metabolism, neuropathology,
and memory and cognition in cell and animal models of ApoE4-dependent AD. This research will further
describe ApoE-IR binding in cells and establish if Shc inhibitors have potential as a novel AD therapeutic
strategy.
AD is split into 2 categories, familial and sporadic. The dominant pathophysiological hypothesis for sporadic
AD, which accounts for >95% of AD cases, is the amyloid cascade hypothesis but this hypothesis is derived
from mutations present in the 1% of cases of familial AD. We investigate an alternative hypothesis for sporadic
AD, the NIR hypothesis. This hypothesis posits that AD is primarily a disease of metabolic dysfunction, driven
by NIR, and that amelioration of NIR can have positive therapeutic outcomes. The ApoE4 allele is the
strongest driver of increased genetic sporadic AD risk 1–4. While there are many theories on how ApoE4
impacts AD pathophysiology, one hypothesis with substantial support is ApoE4 drives NIR 5–10, impairs
downstream neuronal glucose metabolism11–13, and these insulin signaling and consequent metabolic
impairments drive ApoE4's AD pathomechanism6–10,14–20. Recently, published studies and my preliminary data
suggest that ApoE4 protein binds IR and impairs insulin signaling5,8,21. However, we lack a mechanistic
understanding of how ApoE4 drives NIR. My research addresses this gap in knowledge. My working
hypothesis is that ApoE4 binds IR, drives NIR, and causes metabolic perturbations that contribute to AD
pathophysiology.
In Aim 1 I investigate ApoE-IR binding kinetics, site, and the functional effect of this binding to assess its
pathophysiological relevance to AD. In Aim 2 I test whether novel insulin-sensitizing Shc blockers developed
by the Cortopassi lab can rescue parameters of insulin signaling, metabolism, neuropathology, and memory
and cognition in models of ApoE4-dependent AD. The goal of this research is to understand the mechanistic
connection between NIR, ApoE4, and AD (Aim 1) and if insulin-sensitizing Shc blockers can rescue pathology
and clinical signs of ApoE4-dependent AD (Aim 2). The elaboration of this novel therapeutic hypothesis could
open a new strategy in AD therapeutic research not based on dissolution of amyloid, but rather on neuro-
metabolic improvement.

## Key facts

- **NIH application ID:** 10680417
- **Project number:** 5F31AG079625-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Chase A Garcia
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $33,570
- **Award type:** 5
- **Project period:** 2022-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680417

## Citation

> US National Institutes of Health, RePORTER application 10680417, The Role of Apolipoprotein E4 in Neuronal Insulin Resistance and Alzheimer's Disease (5F31AG079625-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10680417. Licensed CC0.

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