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.
