Deep brain stimulation for Alzheimer’s disease – current status and next steps

ABSTRACT

Introduction

Alzheimer’s disease (AD) requires novel therapeutic approaches due to limited efficacy of current treatments.

Areas covered

This article explores AD as a manifestation of neurocircuit dysfunction and evaluates deep brain stimulation (DBS) as a potential intervention. Focusing on fornix-targeted stimulation (DBS-f), the article summarizes safety, feasibility, and outcomes observed in phase 1/2 trials, highlighting findings such as cognitive improvement, increased metabolism, and hippocampal growth. Topics for further study include optimization of electrode placement, and the role of stimulation-induced autobiographical-recall. Nucleus basalis of Meynert (DBS-NBM) DBS is also discussed and compared with DBS-f. Challenges with both DBS-f and DBS-NBM are identified, emphasizing the need for further research on optimal stimulation parameters. The article also reviews alternative DBS targets, including medial temporal lobe structures and the ventral capsule/ventral striatum.

Expert Opinion

Looking ahead, a phase-3 DBS-f trial, and the prospect of closed-loop stimulation using EEG-derived biomarkers or hippocampal theta activity are highlighted. Recent FDA-approved therapies and other neuromodulation techniques like temporal interference and low-intensity ultrasound are considered. The article concludes by underscoring the importance of imaging-based diagnosis and staging to allow for circuit-targeted therapies, given the heterogeneity of AD and varied stages of neurocircuit dysfunction.

KEYWORDS:

• DBS
• Alzheimer‘s disease
• neuromodulation
• memory
• Papez

Article highlights

• AD Pathology and Dysfunction: Alzheimer’s disease (AD) is characterized by beta-amyloid plaque deposition, tau-protein tangles, and neurocircuitry dysfunction across memory, cognitive, and limbic circuits, leading to cognitive decline and memory loss.

• DBS as a Potential Therapy: Deep brain stimulation (DBS) has emerged as a potential therapeutic approach for AD, targeting malfunctioning circuits to ameliorate symptoms. DBS offers precise targeting and titratable therapy delivery.

• Fornix Stimulation Studies: DBS of the fornix has shown promise in preclinical and clinical trials, with evidence suggesting safety, feasibility, and potential cognitive stabilization. Some patients showed hippocampal volume expansion, suggesting a possible neuroregenerative effect.

• NBM Stimulation Studies: DBS of the nucleus basalis of Meynert (NBM) has demonstrated safety and suggested a possible slowing of cognitive decline in AD.

• Future Directions: Future research in DBS for AD may focus on patient selection, parameter optimization, and the development of closed-loop stimulation approaches. Non-invasive neuromodulation techniques like temporal interference and low-intensity focused ultrasound are also promising areas for AD treatment.

Declaration of interest

Andres Lozano is the co-founder of Functional Neuromodulation (a DBS-related company) and is a consultant for Boston Scientific, Medtronic, and Abbott (companies that produce DBS hardware). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.