# Deciphering the enigmatic role of IGF-1 signaling in cognitive decline and Alzheimer's disease

> **NIH NIH R56** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $858,252

## Abstract

PROJECT SUMMARY
The growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling pathway has been strongly implicated in
the modulation of the aging process. However, studies examining the relationship involving IGF-1, the brain and
neurodegenerative diseases, such as Alzheimer's Disease (AD), have proven far more complex. Central
administration of IGF-1 can produce favorable effects on features of normal brain aging. However, early optimism
that raising peripheral IGF-1 could treat AD was dampened when these findings could not be replicated, while
models of reduced IGF-1 signaling actually slowed progression of symptoms in mouse models of human cerebral
Aβ amyloidosis. As opposed to peripheral dosing, we have found that intranasal (IN) treatment with IGF-1 to
target the brain can improve many facets of cognitive aging in mice. However, a paucity of data exists examining
the therapeutic potential of IN IGF-1 in aging, dementia or cerebral amyloidosis. Recent disappointing reports
from an IN insulin trial (“SNIFF”) shift attention toward ligands other than insulin as candidates for IN delivery.
While it is generally accepted that cognitive decline in AD usually appears after some longstanding Aβ
amyloidosis and temporally coincides with the appearance of tauopathy, neuroinflammation, and
neurodegeneration, the etiology of cognitive decline in type 2 diabetes (T2D) may instead be attributed to
vascular dysfunction. To this end, it is worth noting that IGF-1 has not only been shown to promote Aβ uptake
and protect neurons and synapses, but also opposes rarefaction of the vasculature. Therefore, this proposal
aims to directly address the impact of these two critical metabolic hormones to cognitive decline and AD. We
hypothesize that IGF-1 is uniquely positioned to modulate or prevent initiation of some features important to the
pathogenesis of: (1) normal brain aging, (2) age-related cognitive impairment due to Aβ amyloidosis, (3) VCID,
and/or (4) the evolution from presymptomatic to symptomatic phase. We further propose that this “window of
opportunity” may close as pathology progresses. We will test this possibility in Aim 1 by evaluating the ability of
IN insulin versus IGF-1 to delay cognitive decline and related underlying changes in brain aging, using a
combination of functional, molecular, and BOLD-fMRI imaging approaches. In Aim 2 we will further explore the
possibility that a critical `therapeutic window' for IN insulin or IGF-1 treatment may exist in a mouse model of Aβ
amyloidosis, whereby beneficial effects early in disease may—when sustained later into illness—transition in
valence toward ineffective or deleterious. Finally, Aim 3 will evaluate the ability of IN insulin versus IGF-1 to delay
cognitive decline and associated pathologic changes in a mouse model of vascular and mixed dementia. These
studies should better define the central actions of insulin versus IGF-1 and their ability to prevent or delay
cognitive decline in aging, ...

## Key facts

- **NIH application ID:** 10231347
- **Project number:** 1R56AG066431-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** SAMUEL E. GANDY
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $858,252
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231347

## Citation

> US National Institutes of Health, RePORTER application 10231347, Deciphering the enigmatic role of IGF-1 signaling in cognitive decline and Alzheimer's disease (1R56AG066431-01). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10231347. Licensed CC0.

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