# Targeting Type 3 Diabetes (T3D) Mechanism of Alzheimer's Disease (AD) and AD-Related Dementias

> **NIH NIH R43** · REGENE LLC · 2024 · $249,995

## Abstract

Abstract. Given the very limited success in Alzheimer’s disease (AD) drug development over the past decades
an extended search for therapy beyond the amyloid-b and tau hypotheses is needed. According to one promising
and underexplored hypothesis, in AD the key pathophysiological events are linked with brain insulin resistance.
This hypothesis, referred to as Type 3 Diabetes (T3D), is supported by many lines of evidence including altered
insulin pathways in AD brains and cognitive benefits of anti-diabetic drugs. The mechanisms of T3D
pathogenesis remain unknown, however. Extensive research demonstrated that suppression of different nodes
in the growth hormone (GH)/ insulin-like growth factor (IGF)/ mechanistic target of the rapamycin (mTOR)
cascade slows down aging and aging-associated cognitive decline in a range of model organisms. Insulin and
IGF hormonal cascades have a common ancestry and the two axes of hormonal signaling are not fully separated.
Their negative feedback loops overlap, so that activation of IGF-1 receptor (IGF1R) results in suppression of
insulin receptor substrate (IRS) a key node in insulin signaling. Following this evidence, we hypothesize that
chronic activation of a molecular cascade downstream of IGF1 results in a negative feedback
suppression of insulin signaling (Fig. 1) in the brain and T3D development. Additionally, IGF1R negatively
regulates autophagy and positively regulates NF-kB-mediated inflammation providing bridges between T3D,
misfolded proteins, and inflammatory mechanisms of AD and AD-related dementias (ADRD). Informed by this
hypothesis, we have conducted preliminary proof of a principle longevity experiments with mice in which small
molecule IGF1R inhibitors orally administered starting 13 months of age (~45 human years) prevented the
decline of short-term memory, prevented the development of insulin resistance, improved grip strength,
decreased frailty, and increased lifespan. Capitalizing on these results the current proposal will allow us to make
further steps toward the development of AD therapy based on IGF1R inhibition via the following aims: (1) to
optimize drug-candidate molecules via computational modeling and subsequent testing of their target affinity
and selectivity, toxicity properties, absorption, distribution, metabolism, and excretion characteristics; and (2) to
characterize neurodegeneration prevention by optimized molecules using two mouse models: wildtype
mice naturally developing cognitive decline with age and 3xTg-AD mouse model of AD. The ability of optimized
drugs to improve cognitive function and improve markers of insulin signaling, autophagy, inflammation, Aβ, and
tau pathology in their brains will be analyzed. This project will result in a candidate drug(s) for AD and ADRD,
targeting novel molecular mechanisms and ready for preclinical development.

## Key facts

- **NIH application ID:** 10820031
- **Project number:** 1R43AG085738-01
- **Recipient organization:** REGENE LLC
- **Principal Investigator:** Charles Joseph Eyermann
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,995
- **Award type:** 1
- **Project period:** 2024-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820031

## Citation

> US National Institutes of Health, RePORTER application 10820031, Targeting Type 3 Diabetes (T3D) Mechanism of Alzheimer's Disease (AD) and AD-Related Dementias (1R43AG085738-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10820031. Licensed CC0.

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