Gamma oscillations (GO) are electrical signals detected in the brain that are essential for memory and cognition. GO are a product of the activity of a subpopulation of brain cells called parvalbumin interneurons (PVIN).Unsurprisingly, GO and PVIN are both impaired in Alzheimer’s disease (AD). Remarkably, stimulation of PVIN has restored GO and rescued memory in AD preclinical studies. Moreover, PVIN stimulation has attenuated abnormal proteins accumulation (amyloid beta) that are central to AD pathophysiology.

Deep brain stimulation (DBS) is a common neurosurgical procedure where an implanted electrode is used to stimulate a specific area in the brain. Pedunculopontine nucleus (PPN) is an area in the brainstem recognized as being the main driver of GO in the brain. We aim to provide proof of concept for the ability of DBS-PPN to augment PVIN activity and so restore GO, address amyloid beta accumulation, and rescue memory in AD patients.

We are proposing a pilot clinical trial where 5 AD patients will undergo DBS-PPN implantation and followed up for a1-year period. The ability of DBS-PPN to enhance GO will be examined and used as proof of concept for its ability to augment PVIN activity in the brain. Cognitive assessments will also be performed during the study. DBS-PPN serendipitously and consistently improved cognition in Parkinson’s disease patients supporting the safety and feasibility of our approach.

Our study sets the stage for a multi-center randomized controlled trial with the potential of providing the first disease modifying neuromodulatory treatment for AD. Moreover, it paves the way for exploring DBS-PPN in other forms of dementia, for example frontotemporal dementia where PVIN impairment has been reported, and Parkinson’s dementia where preliminary evidence in humans supports a beneficial role.

AD poses significant challenges not only to patients but also to caregivers and the healthcare system. Despite the encouraging breakthrough with the newer drugs, the AD conundrum is far from being resolved. Our study explores a widely utilized treatment modality with an established safety profile to approach AD. Backed with motivating preliminary data in human subjects, our study could potentially provide the first disease modifying neuromodulatory treatment, offering a much-needed relief to all AD stakeholders.