Unlocking cognition by Pulsatile GnRH in Alzheimer's DiseasE

Project Information

UPGRADE

Grant agreement ID: 101123221

DOI

10.3030/101123221

Project closed

EC signature date 4 July 2023

Start date 1 October 2023

End date 31 March 2026

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - UPGRADE (Unlocking cognition by Pulsatile GnRH in Alzheimer's DiseasE)

Reporting period: 2023-10-01 to 2026-03-31

Summary of the context and overall objectives of the project

The cognitive decline associated with Alzheimer’s disease (AD) and other age-related dementias, estimated to affect some 55 million people worldwide, is a growing problem in aging European societies. However, most drugs fail at clinical trial, and currently approved and potential therapeutic strategies aimed at controlling or reversing neurochemical and neurodegenerative changes in the brain have not sustainably or effectively improved cognition in patients, in addition to being associated with significant side effects that increase with the duration of treatment. It is therefore essential to design and test alternative approaches to enhance cognitive performance and reduce the personal, familial and societal burden that AD represents.
Abundant circumstantial or direct evidence connects cognitive decline or AD progression to the age-dependent loss or deregulation of gonadotropin-releasing hormone (GnRH), a neuropeptide better known for its role in the hypothalamic-pituitary-gonadal (HPG) or reproductive axis. Indeed, GnRH neurons also project to brain regions implicated in intellectual functions. Nevertheless, a link between GnRH deregulation and cognitive decline in AD was not seriously considered until our recent study demonstrating that AD-like cognitive deficits in Down syndrome are triggered by progressive GnRH loss, and validating the administration of GnRH in a pulsatile manner using implantable pumps to improve cognitive symptoms in Down syndrome long after their onset. Additionally, this study also demonstrated similar therapeutic effects of low-dose pulsatile GnRH in an animal model of AD. We hypothesize that cognitive reserves in AD patients can also be reactivated and intellectual performance enhanced by restoring GnRH in a physiologically relevant pulsatile pattern.
Specifically, the aims of the UPGRADE project are to:
- Explore the modalities of pulsatile GnRH treatment at the preclinical level in a mouse model of AD, and verifying the resulting functional improvements and their persistence;
- Analyze GnRH activity in an existing AD patient cohort and design a clinical trial of pulsatile GnRH therapy to reactivate cognitive reserves.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have carried out the preclinical experiments planned, expanding our preliminary results regarding the effects of pulsatile GnRH treatment in male mice modeling AD to female and gonadectomized mice, and performing follow-up analyses over more than a year. In addition, we have analyzed hormone levels in AD and control patient samples from the BIOWATCH cohort. Preliminary results from included patients are in agreement with our hypothesis that GnRH secretion is altered in AD, and that restoring physiological levels and rhythms of GnRH in these patients could be beneficial. Further inclusion in this cohort is ongoing.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The results above have led to the first draft of an application for ethics approval for a pilot clinical study testing the effects of pulsatile GnRH therapy in Alzheimer’s disease patients.
In parallel, a start-up, GnRHope, was created in June 2025, in order to continue protecting and exploiting the IPR, in particular by looking for investors to test this potential therapy in patients with other rare dementias, such as frontotemporal dementia.
A major challenge in taking this work forward in patients with Alzheimer’s Disease is the very high cost involved in these trials, which can only be realized in collaboration with large pharmaceutical companies.