Review Article
Deep Brain Stimulation for Alzheimer’s Disease: Tackling Circuit Dysfunction

https://doi.org/10.1111/ner.13305Get rights and content

Abstract

Objectives

Treatments for Alzheimer’s disease are urgently needed given its enormous human and economic costs and disappointing results of clinical trials targeting the primary amyloid and tau pathology. On the other hand, deep brain stimulation (DBS) has demonstrated success in other neurological and psychiatric disorders leading to great interest in DBS as a treatment for Alzheimer’s disease.

Materials and Methods

We review the literature on 1) circuit dysfunction in Alzheimer’s disease and 2) DBS for Alzheimer’s disease. Human and animal studies are reviewed individually.

Results

There is accumulating evidence of neural circuit dysfunction at the structural, functional, electrophysiological, and neurotransmitter level. Recent evidence from humans and animals indicate that DBS has the potential to restore circuit dysfunction in Alzheimer’s disease, similarly to other movement and psychiatric disorders, and may even slow or reverse the underlying disease pathophysiology.

Conclusions

DBS is an intriguing potential treatment for Alzheimer’s disease, targeting circuit dysfunction as a novel therapeutic target. However, further exploration of the basic disease pathology and underlying mechanisms of DBS is necessary to better understand how circuit dysfunction can be restored. Additionally, robust clinical data in the form of ongoing phase III clinical trials are needed to validate the efficacy of DBS as a viable treatment.

Section snippets

INTRODUCTION

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder affecting 10% of people over the age of 65 in the United States and 60–80% of an estimated 43.8 million people with dementia worldwide (1., 2., 3.). Due to its high prevalence and significant morbidity and mortality, the development of effective treatments for AD remains of paramount importance. Since the discovery of pathological hallmarks of AD—cerebral amyloid beta (Aβ) plaques and neurofibrillary tangles containing

Anatomical Spread of Aβ and Tau

The Aβ cascade hypothesis, first proposed in 1991, was based on the discovery of autosomal dominant mutation in genes that are involved in the processing of Aβ (APP, PESN1, and PSEN2) that lead to a familial form of early-onset AD (6). This hypothesis postulated that pathological aggregation of Aβ peptides facilitates the aggregation of hyperphosphorylated tau protein and subsequent neurotoxicity.

Human neuropathological studies have described the temporal and spatial progression of Aβ and tau

Spread of Aβ and Tau

Similar to the spread of pathology in humans, spread of Aβ and tau can be seen in rodent models of AD (143,144). Local injection of Aβ and tau into various brain regions has been shown to propagate in mice, spreading along known network connections and transmitting via serial passage, even in wild-type mice (121,145., 146., 147., 148., 149.). These findings have been replicated using several types of Aβ and tau, including fibrillar, soluble, synthetic, and homogenates from AD patients (121,144.

Antiepileptic Drugs

Given the link between seizure activity and AD, studies have investigated the use of antiepileptic medications in AD patients. In addition to reducing seizures, levetiracetam has been found to reduce hippocampal and entorhinal cortex hyperactivity, decrease low-frequency coherence, increase high-frequency coherence, and increase memory performance (187., 188., 189.). In animal models of AD, levetiracetam has been shown to reverse mitochondrial dysfunction, dendritic hyperexcitability, abnormal

Current Applications

DBS has been utilized since the 1980s to ameliorate circuit dysfunction in basal ganglia circuits to treat extrapyramidal movement disorders (241,242). Currently FDA-approved targets include the subthalamic nucleus (PD), globus pallidus internus (PD, dystonia), ventral intermediate nucleus (PD, essential tremor). Importantly, DBS for PD does not target the primary pathophysiology of alpha-synuclein deposition, but the downstream circuit dysfunction of the basal ganglia. In these patients, DBS

Aβ and Tau Pathology

The increasing evidence for circuit function in AD raises the possibility that such abnormalities contribute to the propagation of Aβ and tau pathology within the corresponding networks. Two studies have provided evidence for such a mechanism in vivo. Investigators have stimulated the entorhinal cortex in a mouse model of AD and showed decreases in hippocampal Aβ and tau, as well as cortical tau (259). Another study targeted the entorhinal cortex and found that stimulation increased synaptic

CURRENT CHALLENGES

Despite our advances, much work remains to investigate DBS as a potential treatment for circuit dysfunction in AD. Foremost, our incomplete understanding of AD pathophysiology limits our ability to critically evaluate the cellular and molecular effects of DBS in AD patients and animal models. In particular, the relationship between circuit dysfunction and Aβ and tau pathology in AD remains to be determined, as it likely contributes to propagation of pathology in a complex manner. Disease

FUTURE DIRECTIONS

Based on the age-discrepant results of the ADvance trial (phase II), the ADvance II (phase III) trial is currently recruiting patients over 65 with mild dementia for bilateral forniceal DBS (280). As the largest trial of DBS for AD to date, this study will follow an estimated 210 patients after forniceal DBS with a primary endpoint of Integrated Alzheimer’s Disease Rating Scale (iADRS) at 12 months. The results of this study will be pivotal in validating the efficacy of DBS as a viable

CONCLUSIONS

There is accumulating clinical evidence of circuit dysfunction in AD, including at the neurotransmitter, cellular, and network level. Intriguingly, a number of animal studies have provided evidence that circuit modulation may even slow or reverse the underlying disease pathophysiology. Such treatments are urgently needed given the enormous human and economic cost of AD and the disappointing results of trials targeting Aβ and tau to date. Further exploration of the basic disease pathology, as

Authorship Statements

Dr. J. Lam, Dr. J. Lee, Dr. C.Y. Liu, Dr. A.M. Lozano, and Dr. D.J. Lee contributed to the conception and design of the review. Dr. J. Lam and Dr. J. Lee performed the literature search and drafted the manuscript. Dr. C.Y. Liu, Dr. A.M. Lozano, and Dr. D.J. Lee provided assistance in interpretation of the literature and drafting of the manuscript. Dr. J. Lam, Dr. J. Lee, Dr. C.Y. Liu, Dr. A.M. Lozano, and Dr. D.J. Lee critically revised the manuscript, approved the final manuscript and agree to

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