# Therapeutic Potential of FGF21 for Alzheimer’s Disease

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $590,721

## Abstract

Project Summary / Abstract
Cognitive dysfunction and dementia rates are increasing worldwide in part due to the significant increase
in life expectancy. Alzheimer’s disease (AD), the main cause of dementia, is a progressive
neurodegenerative brain disease characterized by impairments in cognitive function. Aging is the main risk
factor for AD and unfortunately there is no effective treatment for slowing down aging or treating AD.
Current approaches to treat AD (e.g., amyloid beta accumulation and tau hyperphosphorylation) have been
unsuccessful which calls for novel approaches to treat the full spectrum of this disease. Recent studies
have postulated that cognitive decline and AD might be manifestations of metabolic disorders. In particular,
changes in glucose metabolism and brain insulin sensitivity have been identified as common features
observed in AD. Our published works reveal that the endocrine hormone fibroblast growth factor 21
(FGF21) decreases body weight during obesity, improves insulin sensitivity, and corrects metabolic
dysfunctions in animal models. Clinical trials with FGF21 mimetics have also demonstrated the efficacy of
targeting this pathway to improve metabolic profiles in humans. Interestingly, recent data suggests that
FGF21 administration may also prevent neurodegeneration and pathological deficits in animal models of
AD. While circulating FGF21 levels are derived primarily by the liver, our recently published study reveals
the unexpected discovery that FGF21 is also expressed in a very specific region of the central nervous
system. Specifically, FGF21 is expressed in the retrosplenial cortex and can signal to the hippocampus
and can regulate learning and memory. A previous study demonstrates that FGF21 is induced from
neurons in response to mitochondrial stress. These observations are the backbone of our main hypothesis
in this proposal which seeks to interrogate whether FGF21 signals to neurons in hippocampus to not only
improve neuronal metabolism and memory, but also improves AD symptoms. This proposal employs
various genetic AD mouse models to explore different aspects of AD, as well as genetic and
pharmacological approaches, to investigate the effects of FGF21 and in the improvement of memory and
cognition. Together, these studies will not only further our knowledge of the role of FGF21 in neuronal
metabolism but will also provide a better understanding of potential metabolic abnormalities during AD.
Finally, these studies may reveal a potential therapeutic approach to treat AD and its related dementias.

## Key facts

- **NIH application ID:** 10886772
- **Project number:** 5R01AG083950-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Matthew Joseph Potthoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $590,721
- **Award type:** 5
- **Project period:** 2023-07-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886772

## Citation

> US National Institutes of Health, RePORTER application 10886772, Therapeutic Potential of FGF21 for Alzheimer’s Disease (5R01AG083950-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10886772. Licensed CC0.

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