Unlocking cognition by Pulsatile GnRH in Alzheimer's DiseasE

Introduction

Cognitive decline associated with Alzheimer disease (AD) and other age-related dementias affects ~55 million people worldwide, and is a growing problem in aging European societies. However, most drugs fail at clinical trials, and approved treatments aimed at controlling or reversing pathological changes in the brain do not improve cognition in patients, besides having significant side effects.

Need for Alternative Approaches

It is thus essential to design and test alternative approaches to enhance cognitive performance and reduce the personal, familial, and societal burden of AD. There is abundant circumstantial evidence pointing to a correlation between cognitive decline or AD progression with the age-dependent loss or deregulation of gonadotropin-releasing hormone (GnRH), a neuropeptide better known for its role in the reproductive axis.

Research Findings

Nevertheless, a link between the two processes has not been seriously considered. In a recent groundbreaking study, we have shown that AD-like cognitive deficits in Down syndrome stem from progressive GnRH loss. Restoring native GnRH in a physiologically relevant pulsatile pattern using implantable pumps safely and effectively improves cognition long after the onset of symptoms, together with augmented brain connectivity.

Observations in AD Patients

Additionally, we have shown that tanycytes, specialized hypothalamic glial cells that control GnRH secretion, are fragmented in AD patient brains. Putting these two findings together, we hypothesize that cognitive performance in AD patients can also be enhanced by administering pulsatile GnRH at normally occurring doses, improving their quality of life.

Project Goals

The UPGRADE project will:

1. Extend promising results we have obtained on the effectiveness of this strategy in a preclinical mouse model of AD.
2. Analyze GnRH activity and pulsatility in an existing cohort of AD patients.
3. Draft a clinical trial protocol to test the safety and efficacy of pulsatile GnRH therapy to reactivate cognitive reserves in patients with mild/moderate AD.