Brain Stimulation in Alzheimer’s Disease Trials

Abstract

Alzheimer’s disease (AD) continues to lack definitive curative therapies, necessitating an urgent exploration of innovative approaches. This review provides a comprehensive analysis of recent clinical trials focusing on invasive and non-invasive brain stimulation techniques as potential interventions for AD. Deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) are evaluated for their therapeutic efficacy, safety, and applicability. DBS, though invasive, has shown promising results in mitigating cognitive decline, but concerns over surgical risks and long-term effects persist. On the other hand, non-invasive methods like rTMS, tDCS, and tACS have demonstrated potential in enhancing cognitive performance and delaying disease progression, with minimal side effects, but with varied consistency. The evidence hints towards an individualized, patient-centric approach to brain stimulation, considering factors such as disease stage, genetic traits, and stimulation parameters. The review also highlights emerging technologies and potential future directions, emphasizing the need for larger, multi-center trials to confirm preliminary findings and establish robust clinical guidelines. In conclusion, while brain stimulation techniques present a promising avenue in AD therapy, further research is imperative for more comprehensive understanding and successful clinical implementation. Through this review, we aim to catalyze the scientific discourse and stimulate further investigation into these novel interventions for AD.

Keywords

Alzheimer’s disease brain stimulation deep brain stimulation repetitive transcranial magnetic stimulation transcranial alternating current stimulation transcranial direct current stimulation

INTRODUCTION

Alzheimer’s disease (AD) represents the most prevalent form of dementia worldwide, marked by insidious cognitive deterioration and memory loss [1]. With the swift demographic transition towards an older global population, the AD burden is forecasted to escalate dramatically, exerting substantial strain on healthcare infrastructures and societies [2]. The etiology of AD is intricate and multifaceted, stemming from an interplay of genetic predispositions and environmental influences that culminate in the pathological signatures of amyloid-β plaques and neurofibrillary tangles [3]. These hallmarks disrupt neuronal function and connectivity, leading to the cognitive deficits characteristic of AD.

Despite the substantial advancements in our comprehension of AD pathology, the development of effective therapeutic interventions remains a formidable challenge. Over the past twenty years, an array of pharmacological agents targeting the amyloid-β pathway have undergone clinical trials, but the majority have fallen short in demonstrating significant efficacy in stalling or reversing disease progression [4, 5]. More recently, however, there has been renewed optimism with the advent of novel therapeutics such as aducanumab, lecanemab, and donanemab, which have shown potential in mitigating disease progression [6 –9]. Nevertheless, these findings, while encouraging, are preliminary, and time will be necessary before these agents can be integrated into routine clinical practice.

The repeated setbacks in pharmacological trials underscore the urgency to explore and invest in innovative therapeutic strategies. This realization has sparked an intensified interest in non-pharmacological interventions, particularly the application of brain stimulation techniques as potential therapeutic modalities for AD. Both invasive techniques, such as deep brain stimulation (DBS), and non-invasive methods, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS), are being rigorously investigated for their potential to ameliorate cognitive deficits and improve quality of life in patients with AD [10]. These techniques offer the prospect of modulating neural circuits implicated in AD, providing a novel avenue of treatment that goes beyond the conventional pharmacological paradigm [11].

Although the exact mechanisms by which brain stimulation exerts its therapeutic effects in AD are still not fully understood, these approaches represent an exciting frontier in AD research. This manuscript will provide an in-depth review of the current state of published therapeutic trials in AD, focusing on both invasive and non-invasive brain stimulation techniques, and discuss their potential implications for future AD therapy. It is hoped that this comprehensive overview will provide valuable insights for researchers and clinicians working towards the ultimate goal of finding an effective treatment for this debilitating disease.

INVASIVE BRAIN STIMULATION

Invasive brain stimulation represents a category of therapeutic techniques that entail surgical intervention to modulate the activity of specific brain regions. This category includes methods such as DBS, which directly delivers electrical stimulation to targeted areas within the brain. Such invasive techniques have proven effective in managing various neurological disorders, providing a robust, targeted modality for altering pathological neural circuits. However, the invasive nature of these techniques also introduces inherent surgical risks and necessitates a comprehensive assessment of the risk-benefit ratio for each individual patient.

Deep brain stimulation (DBS)

DBS is a neurosurgical procedure primarily used in the treatment of movement disorders, such as Parkinson’s disease and essential tremor. DBS involves the implantation of electrodes into specific brain regions that are associated with pathological neural activity. These electrodes are connected to an implantable pulse generator or “pacemaker” that can be programmed to deliver continuous high-frequency electrical pulses, modulating the abnormal neural activity and thereby alleviating motor symptoms [12] (see Fig. 1).

Fig. 1

Invasive and non-invasive brain stimulation techniques. DBS, deep brain stimulation; TMS, transcranial magnetic stimulation; rTMS, repetitive transcranial magnetic stimulation; iTBS, intermittent theta burst stimulation; TES, transcranial electrical stimulation; tDCS, transcranial direct current stimulation; tACS, transcranial alternate current stimulation.

In the context of AD, DBS is theorized to work by modulating the activity of specific neural circuits implicated in cognition and memory. Moreover, mechanisms such as increased neurotransmitter release, release of growth factors, neurogenesis. and neurotransmitter respecification have been outlined [13].

One of the main reasons that DBS is considered for AD treatment is its ability to target precise brain regions. In the context of AD, three primary targets have been identified: the fornix, the nucleus basalis of Meynert (NBM), and the ventral capsule/ventral striatum (VC/VS) region. Each of these regions plays a distinct role in cognition and memory, and disruption in their functioning is believed to contribute to the cognitive impairments seen in AD. The fornix, a critical component of the Papez circuit involved in memory formation, was the target in the initial AD DBS trials following observations that stimulation of this area in a patient with obesity led to unexpected improvements in memory [14]. The fornix acts as a major output tract of the hippocampus, a region deeply involved in memory formation and retrieval. By stimulating the fornix, DBS can enhance the activity of the hippocampus and improve memory functions. Similarly, the NBM and VC/VS region are involved in different aspects of cognition. The NBM is a major source of acetylcholine in the brain, a neurotransmitter that is depleted in AD and is crucial for many cognitive processes. On the other hand, the VC/VS region is part of the brain reward system and is involved in motivation and mood, both of which can be affected in AD.

In the realm of AD, there is a growing body of preclinical data based on experimental disease models, mainly in animals. The studies conducted on these models have helped in understanding the potential mechanisms and effects of DBS in the treatment of AD. Animal models have demonstrated that DBS can influence neural circuits and enhance neuroplasticity, reducing amyloid deposition in the hippocampus and cortex, decreasing astrogliosis and microglial activation, thus reducing neuronal loss [15 –18].

Stemming from this evidence, in a Phase II clinical trial, Lozano et al. administered DBS to the fornix of 42 patients with mild AD. Over 12 months, they found that while the overall group did not show a significant improvement in cognition, a subgroup of patients aged 65 or older demonstrated a slower decline in cognitive scores compared to a matched historical control group. Furthermore, DBS was associated with increased cerebral glucose metabolism, a marker of neural activity, in brain regions affected by AD, indicating potential disease-modifying effects [19].

Another target, the NBM, is the primary source of cholinergic innervation to the cerebral cortex and is severely affected in AD. Kuhn et al. performed a pilot study of NBM DBS in six patients with mild to moderate AD. Over six months, they observed stabilization of cognitive scores in three patients and improved cerebral glucose metabolism evaluated with FDG-PET in all patients [20].

A single research study has evaluated the impact of VC/VS-DBS on cognitive outcomes in patients with AD. The aim of targeting the VC/VS regions is to modify frontal networks and, thereby, influence executive functioning in individuals with AD. Scharrre and colleagues carried out a Phase I prospective, non-randomized, open-label intervention on three patients over a minimum period of 18 months. All three participants exhibited a slower rate of cognitive deterioration, as compared to the control group, when assessed using the clinical dementia rating scale sum of boxes (CDR-SB) score.

For an overview of published studies employing DBS in AD, see Table 1.

Table 1

Studies employing deep brain stimulation (DBS) in Alzheimer’s disease treatment

Study	N. of patients	Target area	Disease stage	Experimental design	Stimulation parameters	Main outcomes
Turnbull et al. 1985 [81]	1	NBM	Mild-moderate AD	Open-label	50 Hz×15 s ON and 12 min OFF (day and night)	Global cognition, EEG, FDG-PET
Laxton et al. 2010 [82]	6	Fornix	Mild AD [83]	Open-label	130 Hz×12 months	MMSE, ADAS-cog, FDG-PET
Fontaine et al. 2013 [84]	1	Fornix	Mild AD [85]	Open-label	130 Hz×12 months	MMSE, ADAS-Cog, FCSRT, FDG-PET
Sankar et al. 2015 [86]	6	Fornix	Mild AD [83]	Open-label	130 Hz×12 months	MMSE, ADAS-cog, MRI, FDG-PET
Kuhn et al. 2015 [20]	6	NBM	Mild-moderate AD [83,85, 83,85]	Randomized, double-blind, sham-controlled	20 Hz×2 weeks (sham-controlled) and 48 weeks (open-label)	ADAS-cog, EEG, FDG-PET
Kuhn et al. 2015 [87]	2	NBM	Mild AD	Open-label	20 Hz×26–28 months	ADAS-cog, MMSE
Hardenacke et al. 2016 [88]	8	NBM	Mild AD	Open-label	20 Hz×24 months	ADAS-cog
Lozano et al. 2016 [19]	42	Fornix	Mild AD [89]	Randomized, double-blind, sham-controlled	130 Hz×12 months	ADAS-cog, CDR-SB, MRI, FDG-PET
McMullen et al. 2016 [90]	1	Fornix	AD	Open-label	Not reported×12 months	ADAS-cog, MRI, FDG-PET
Ponce et al. 2016 [91]	1	Fornix	AD	Randomized, double-blind, sham-controlled	130 Hz×12 months	Safety
Dürschmid et al. 2017 [92]	2	NBM	AD	Randomized, double-blind, sham-controlled	20 Hz	EEG
Baldermann et al. 2018 [93]	10	NBM	AD [83,85, 83,85]	Open-label	20 Hz×12 months	MMSE, ADAS-cog, ADAS-mem, MRI
Leoutsakos et al. 2018 [94]	42	Fornix	Mild AD [95]	Randomized, double-blind, sham-controlled	130 Hz×24 months	ADAS-cog, CDR-SB, CVLT, NPI
Scharre et al. 2018 [96]	3	VC/VS	AD [83] with biomarkers	Open-label	Individualized×18 months	CDR, FDG-PET
Mao et al. 2018 [97]	5	Fornix	Severe AD [98]	Open-label	130 Hz×1.5–3 months	MMSE, MoCA, CDR

NBM, nucleus basalis of Meynert; VC/VS, ventral capsule/ventral striatum; EEG, electroencephalography; FDG-PET, fluorodeoxyglucose-positron emission tomography; MMSE, Mini-Mental State Examination; ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; CDR-SB, Clinical Dementia Rating-sum of boxes; ADAS-mem, Alzheimer’s Disease Assessment Scale-memory subscale; MRI, magnetic resonance imaging; CVLT, California Verbal Learning Test; NPI, Neuropsychiatric Inventory; MoCA, Montreal Cognitive Assessment.

While these preliminary studies suggest potential benefits of DBS in AD, further research is needed to confirm these findings and to optimize the procedure. Several questions remain unanswered, such as the ideal timing of intervention, the most effective stimulation parameters, and the long-term safety and efficacy of DBS in AD. Additionally, more robust randomized controlled trials are required to validate the therapeutic effects observed in the initial studies. It is also worth noting that while DBS has shown promise, it is an invasive procedure that carries risks, including infection, hemorrhage, and neurological deficits. Therefore, it is crucial to thoroughly assess the risk-benefit ratio for each individual patient.

NON-INVASIVE BRAIN STIMULATION

Compared to invasive brain stimulation techniques as DBS, non-invasive brain stimulation techniques offer a potentially safer, less physically intrusive method for modulating brain activity. These methods encompass a suite of procedures that, by their nature, require no surgical intervention, thereby minimizing risks associated with surgery, such as infection or hemorrhage. Techniques such as rTMS, tDCS, and tACS can be applied externally, directly through the scalp.

These non-invasive techniques rely on different principles to influence brain activity, yet all aim to modulate neural circuits, potentially enhancing cognitive functions or mitigating symptoms of neurodegenerative disorders such as AD. While the concept of influencing brain activity externally may initially seem less potent than the direct, internal influence of DBS, numerous studies have demonstrated the potential efficacy of these non-invasive methods in various psychiatric and neurological conditions [21]. Importantly, due to their non-invasive nature, these techniques are typically associated with fewer side effects and complications compared to invasive procedures like DBS [22]. This makes them a more appealing option for many patients and practitioners, and allows for broader application, as they can be administered in a wider range of settings, including outpatient clinics.

However, while non-invasive brain stimulation techniques offer certain advantages over invasive methods, it is crucial to note that our understanding of their mechanisms of action, as well as their long-term safety and efficacy, remains incomplete [23, 24]. As with any treatment modality, further research is needed to optimize these techniques, establish their role in therapeutic algorithms, and fully elucidate their potential benefits and limitations in the context of neurodegenerative diseases like AD.

Repetitive transcranial magnetic stimulation (rTMS)

rTMS is a non-invasive neuromodulation technique that has gained significant attention in recent years as a potential therapeutic tool for AD. rTMS employs a coil placed on the scalp to generate brief, high-intensity magnetic fields that can penetrate the skull and induce electrical currents in the underlying cortical tissue [25]. Depending on the frequency of stimulation, rTMS can either increase (via high-frequency stimulation) or decrease (via low-frequency stimulation) the excitability of the targeted cortical area, thereby modulating the neural activity within these regions [26]. An extension of this technique, theta-burst stimulation (TBS), can be delivered in two forms: intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS). Much like high and low-frequency rTMS, iTBS is generally believed to increase cortical excitability, while cTBS is thought to decrease it [27] (see Fig. 1).

rTMS represents a potent tool for influencing neuronal dynamics in AD through a multi-faceted approach. It plays an essential role in modulating cortical plasticity, a key substrate for the brain’s adaptive reorganization. In AD, disruptions to the synapse-rich neuronal networks contribute to the diminished plasticity often observed. The capacity of rTMS to induce depolarization or hyperpolarization of neurons makes it capable of facilitating synaptic enhancement or reduction, thus effectively stimulating plastic changes and potentially restoring deteriorated cognitive functions. Beyond enhancing cortical plasticity, rTMS also intervenes in modulating neural connectivity, a critical aspect in restoring the dysfunctional long-range connections characteristic of AD. By adjusting the flow of neural information, rTMS aids in reinstating the lost coherence among different brain regions, thereby potentially mitigating cognitive decline and memory loss. In conjunction with these mechanisms, rTMS capitalizes on its influence on cortical reactivity, thereby heightening the brain cortex’s responsiveness to stimuli. The stimulation provided by rTMS pulses can enhance not only the focal area under the coil but also distant cortical regions via synaptic connections. In the context of AD, this increased cortical reactivity could serve as a driving force in reactivating areas of diminished activity, offering an avenue to increase cognitive functions [28]. Lastly, the capacity of rTMS to influence neurotransmission underscores its potential therapeutic utility in AD. The process is mediated by its ability to stimulate the release of neurotransmitters such as glutamate, GABA, and dopamine. Given the notable deficits in neurotransmitter systems in AD, particularly acetylcholine, a vital player in memory and learning, the potential for rTMS to correct these impairments adds another layer to its therapeutic applicability [29].

Substantial experimental data gathered from animal models of AD have offered critical insights into the therapeutic potential of rTMS. Studies in rodents, for instance, have demonstrated the potential of rTMS in enhancing neuroplasticity, improving cognitive performance, and mitigating pathological hallmarks of AD, such as amyloid-β plaque accumulation and tau hyperphosphorylation [30]. Although these findings may not fully extrapolate to human conditions, they nevertheless provide a robust experimental foundation for the therapeutic application of rTMS in AD.

In the pursuit of effective interventions for AD, researchers have utilized rTMS to target various key regions of the brain, each of which plays a distinct role in cognitive processes and the overall pathology of AD. The dorsolateral prefrontal cortex (DLPFC), a region integral to working memory and executive function, has been a primary target in many of these investigations [31 –44]. Some studies have extended their focus to include the parietal cortex, another region implicated in AD due to its role in spatial attention and episodic memory [45 –47]. The precuneus, a central node within the default mode network and a region associated with the early onset of AD pathology, has also emerged as a promising target due to its crucial role in episodic memory [48, 49]. These diverse focal points of rTMS application reflect the multifaceted nature of AD and the necessity for a broad-based approach in treatment strategies.

In the early stages of research into rTMS as a treatment for AD, a pivotal study was conducted by Cotelli and colleagues in 2006 [31]. This study focused on the high-frequency rTMS effect over the left DLPFC. After a single session or rTMS, patients exhibited significant enhancement in their action naming capabilities, an aspect of cognitive function that is usually adversely affected in this disease. This groundbreaking study was the first to suggest that rTMS could be a viable method of enhancing cognitive function in AD [31].

In a subsequent randomized controlled trial by the same research group in 2011, the application of high-frequency rTMS was extended to bilateral DLPFC and the parietal cortex. This intervention, administered over a period of 4 weeks, yielded significant enhancements in various cognitive measures in patients with AD, including the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). Importantly, these beneficial effects persisted for as long as 8 weeks following the cessation of the treatment [43].

In a larger scale randomized controlled trial by Rabey et al. in 2013, the therapeutic potential of rTMS in AD was further corroborated [32]. High-frequency rTMS was administered to the bilateral DLPFC and bilateral parietal cortex for 6 weeks in patients with mild to moderate AD. The resultant improvements were marked in the ADAS-Cog and the clinical global impression scale, and impressively, these effects were maintained for a substantial period of 4.5 months after treatment completion [32].

Additional, substantially larger, clinical trials have further enhanced our understanding of the potential therapeutic role of rTMS in AD. For instance, Bagattini et al. explored the synergistic effect of cognitive training and left DLPFC rTMS as a combined intervention in 50 patients with AD. The study underscored the value of rTMS as an add-on treatment to enhance the effects of cognitive training in patients with AD. Participants who underwent the combined therapy displayed significant improvements in cognitive performance compared to those who received cognitive training alone, supporting the hypothesis that rTMS can boost the efficacy of cognitive training interventions [39].

In a similar vein, Sabbagh et al. investigated the combined effects of rTMS and cognitive training in 129 patients with AD. Their study corroborated the findings of Bagattini et al., indicating that combined therapy led to substantial cognitive improvements, thereby enhancing the quality of life in patients with AD. This combined intervention appears to have an additive effect, enhancing overall cognition beyond the capabilities of each standalone treatment [40].

Koch et al. conducted a pivotal study where they targeted the precuneus, a brain region that is implicated in the memory network and is known to be affected early in AD. They delivered high-frequency rTMS over the precuneus for two weeks in patients with AD. The results showed significant improvements in episodic memory tasks, providing evidence that targeting this specific brain region could be beneficial in AD [49].

In a later study, Koch et al. carried out a larger, randomized, double-blind, sham-controlled Phase II trial which evaluated the safety and efficacy of precuneus rTMS in 50 mild-to-moderate patients with AD over 24 weeks. The trial comprised a 2-week intensive course with daily rTMS (or sham) applications, followed by a 22-week maintenance phase with weekly applications. The study demonstrated that the group receiving precuneus rTMS maintained their performance on the CDR-SB ADAS-Cog, Mini-Mental State Examination (MMSE), and Alzheimer’s disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL), while the sham group displayed a decline. Furthermore, precuneus cortical excitability remained stable in the rTMS group, and local gamma oscillations were enhanced [48].

Finally, a recent double-blind, randomized, sham-controlled study investigated the impact of high-frequency rTMS on cognitive functions and functional connectivity in 56 patients with AD. The rTMS was applied to the left lateral parietal region, selected for its high functional connectivity with the hippocampus as per resting-state fMRI. Participants underwent multimodal MRI scans and neuropsychological tests at baseline, immediately after the intervention, and at a 12-week follow-up. Findings showed that the active rTMS treatment group exhibited increased MMSE scores and heightened dynamic functional connectivity (dFC) within the default mode network (DMN) compared to the sham treatment group immediately after the intervention. However, these enhancements were not sustained at the 12-week follow-up. Notably, a significant positive correlation between changes in MMSE and changes in the dFC magnitude of DMN was found in the active-rTMS group, suggesting that DMN functional connectivity may contribute to the short-term cognitive improvements observed with rTMS treatment in patients with AD [47].

For an overview of published studies employing rTMS in AD, see Table 2.

Table 2

Studies employing repetitive transcranial magnetic stimulation (rTMS) in Alzheimer’s disease treatment

Study	N. of patients	Target area	Disease stage	Experimental design	Stimulation parameters	Main outcomes
Cotelli et al. 2006 [31]	15	L/R DLPFC	Mild-moderate AD [83]	Randomized, single-blind, sham-controlled	20 Hz, 10 pulses×1 train×1 session	Naming, MMSE
Cotelli et al. 2008 [99]	12	L/R DLPFC	Mild/moderate-severe AD [83]	Randomized, single-blind, sham-controlled	20 Hz, 10 pulses×1 train×1 session	Naming, MMSE
Cotelli et al. 2011 [43]	10	L DLPFC	AD [83]	Randomized, double-blind, sham-controlled	20 Hz, 40 pulses×50 trains×20 sessions (4 weeks)	BADA, MMSE
Bentwich et al. 2012 [100]	8	Bro, Wer, L/R DLPFC, L/R PC	Mild AD [85]	Open-label	10 Hz, 20 pusles×20 trains×30 sessions (6 weeks)	ADAS-cog, CGIC
Ahmed et al. 2011 [33]	45	L/R DLPFC	AD [83]	Randomized, double-blind, sham-controlled	20 Hz and 1 Hz, 2000 pulses×5 sessions (5 days)	MMSE, IADL, GDS
Rabey et al. 2013 [32]	15	Bro, Wer, L/R DLPFC	Mild-moderate AD [85]	Randomized, double-blind, sham-controlled	10 Hz, 400/500 pulses×54 sessions (6 weeks + 3 months maintenance)	ADAS-cog, CGIC, NPI
Eliasova et al. 2014 [101]	10	R IFG	MCI [102] and mild AD [103]	Randomized, sham-controlled	10 Hz, 50 pulses×45 trains×1 session	Stroop, TMT, CVSET
Devi et al. 2014 [104]	12	L/R DLPFC	AD [83]	Open-label, sham-controlled	10 Hz, 50 pulses×20 trains×4 sessions (2 weeks)	BDAE, MRI
Rutherford et al. 2015 [34]	10	L/R DLPFC	AD	Randomized, double-blind, sham-controlled	20 Hz, 40 pulses×50 trains×16 sessions (4 weeks)	ADAS-cog, MoCA, RMBC
Wu et al. 2015 [35]	52	Left DLPFC	AD [105]	Randomized, double-blind, sham-controlled	20 Hz, 1200 pulses×1 train×1 session	BEHAVE-AD
Anderkova et al. 2015 [106]	20	R IFG, R STG, VTX	MCI [107] and mild AD [103]	Sham-controlled	10 Hz, 50 pulses×45 trains 1 session	TMT, Stroop, MRI
Lee et al. 2016 [36]	27	Bro, Wer, L/R DLPFC, L/R PC	Mild-moderate AD [85]	Randomized, double-blind, sham-controlled	10 Hz, 20 pulses×60 trains×30 sessions (6 weeks)	ADAS-cog, MMSE, CGIC
Zhao et al. 2017 [45]	30	PC and TC	Mild-moderate AD [85]	Randomized, double-blind, sham-controlled	20 Hz, 200 pulses×20 trains×30 sessions (6 weeks)	ADAS-cog, MMSE, MoCA, AVLT
Koch et al. 2017 [49]	14	Precuneus	Prodromal AD [108] with biomarkers	Randomized, double-blind, sham-controlled	20 Hz, 40 pulses×40 trains×10 sessions (2 weeks)	ADCS-PACC, EEG, TMS/EEG
Alcalá-Lozano et al. 2018 [109]	19	L DLPFC	AD	Randomized, single-blind	5 Hz, 50 pulses×30 trains×15 sessions (3 weeks)	ADAS-cog, MMSE, NPI, GDS, CGIC
Zhang et al. 2019 [37]	28	L DLPFC, L TC	AD [110]	Randomized, double-blind, sham-controlled	10 Hz, 50 pulses×20 trains×40 sessions (4 weeks)	ADAS-cog, MMSE, ACE-III, NPI, MRI
Turriziani et al. 2019 [111]	24	L/R DLPFC	AD [105]	Randomized, sham-controlled	1 Hz, 600 pulses×1 train×10 sessions (2 weeks)	Memory, MMSE, RAVLT, other
Padala et al. 2020 [38]	20	L DLPFC	AD	Randomized, double-blind, sham-controlled	10 Hz, 40 pulses×75 trains×20 sessions (4 weeks)	AES-C, MMSE, IADL, CGIC
Bagattini et al. 2020 [39]	50	L DLPFC	MCI [112] and mild-moderate AD [83]	Randomized, double-blind, sham-controlled	20 Hz, 40 pulses×50 trains×20 sessions (4 weeks)	FNAT, MMSE, RAVLT, TMT, other
Wu et al. 2020 [113]	13	L DLPFC	Mild-moderate AD [105]	Open-label	iTBS 600 pulses×3 trains×14 sessions (2 weeks)	MMSE, MoCA, GDS, NPI, MRI
Brem et al. 2020 [114]	34	Bro, Wer, L/R DLPFC, L/R PC	Mild-moderate AD [83]	Randomized, double-blind, sham-controlled	10 Hz, 20 pulses×65 trains×30 sessions (6 weeks)	ADAS-cog, CGIC, TMS
Sabbagh et al. 2020 [40]	129	Bro, Wer, L/R DLPFC, L/R PC	Mild-moderate AD [85]	Randomized, double-blind, sham-controlled	10 Hz, 20 pulses×65 trains×30 sessions (6 weeks)	ADAS-cog, CGIC
Jia et al. 2021 [46]	69	L PC	Mild-moderate AD [115]	Randomized, double-blind, sham-controlled	10 Hz, 20 pulses×40 trains×10 sessions (2 weeks)	MMSE, CDR, PVLT
Li et al. 2021 [41]	75	L DLPFC	AD [115]	Randomized, double-blind, sham-controlled	20 Hz, 10 pulses×100 trains×30 sessions (6 weeks)	ADAS-cog, MMSE
Leocani et al. 2021 [116]	30	L/R PFC	AD [105]	Randomized, double-blind, sham-controlled	10 Hz, 20 pulses×42 trains×16 sessions (8 weeks)	ADAS-cog, MMSE, BDI
Zhou et al. 2021 [42]	65	L/R DLPFC	Mild-moderate AD	Randomized, double-blind, sham-controlled	10 Hz, 150 pulses×10 trains×20 sessions (4 weeks)	PSQI, ADAS-cog
Teti Mayer et al. 2021	12	L DLPFC	Mild-moderate AD [83]	Open-label, uncontrolled	10 Hz, 50 pulses×40 trains×10 sessions (5 days)	MMSE, MDRS, QoL, other
Wu et al. 2022 [44]	47	L DLPFC	Mild-moderate AD [105]	Randomized, double-blind, sham-controlled	iTBS 600 pulses×3 trains×14 sessions (2 weeks)	AM, MMSE, MoCA, CDR, NPI, other
Vecchio et al. 2022 [117]	63	Bro, Wer, L/R DLPFC, L/R PC	Mild-moderate AD [83]	Randomized, double-blind, sham-controlled	10 Hz, 20 pulses×65 trains×30 sessions (6 weeks)	ADAS-cog, EEG
Qin et al. 2022 [118]	17	L DLPFC, L TC	Mild-moderate AD [110]	Randomized, double-blind, sham-controlled	10 Hz, 50 pulses×20 trains×20 sessions (4 weeks)	MRI, ADAS-cog, NPI, ACE-III, other
Suarez Moreno et al. 2022 [119]	30	Bro, Wer, L/R DLPFC, L/R PC	AD	Open-label, uncontrolled	10 Hz, 20 pulses×65 trains×30 sessions (6 weeks)	ADAS-cog, MMSE, apathy
Yao et al. 2022 [120]	27	Cerebellum	AD [121]	Randomized, double-blind, sham-controlled	5 Hz, 20 pulses×100 trains	ADAS-cog, MMSE, MoCA, MRI, other
Mimenza-Alvarado et al. 2022 [122]	34	L DLPFC	MCI [123] and mild AD [105,115, 105,115]	Randomized, double-blind, sham-controlled	125 Hz, 375 pulses×450 trains×360 sessions (6 months)	ADAS-cog, FAB, VF, ADL, GDS,
Koch et al. 2022 [48]	50	Precuneus	Mild-moderate AD [124] with biomarkers	Randomized, double-blind, sham-controlled	20 Hz, 40 pulses×40 trains×32 sessions (24 weeks)	CDR-SB, ADAS-cog, TMS/EEG, other
Wei et al. 2022 [47]	69	L PC	Mild-moderate AD [115]	Randomized, double-blind, sham-controlled	10 Hz, 20 pulses×40 trains×10 sessions (2 weeks)	MMSE, PVLT, MRI,

L, left; R, right; DLPFC, dorsolateral prefrontal cortex; Bro, Broca’s area; Wer, Wernicke’s area; PFC, prefrontal cortex; PC, parietal cortex; IFG, inferior frontal gyrus; STG, superior temporal gyrus; VTX, vertex; TC, temporal cortex; MMSE, Mini-Mental State Examination; BADA, Battery for Analysis of Aphasic Deficits; ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; CGIC, Clinical Global Impression of Change scale; IADL, Instrumental Activities of Daily Living; GDS, Geriatric Depression Scale; NPI, Neuropsychiatric Inventory; TMT, Trail Making Test; CVSET, Complex Visual Scene Encoding Task; BDAE, Boston Diagnostic Aphasia Examination; MoCA, Montreal Cognitive Assessment; RMBC, Revised Memory and Behavior Checklist; BEHAVE-AD, Behavioral pathology in Alzheimer’s disease rating scale; AVLT, Auditory Verbal Learning Test; ADCS-PACC, Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite; ACE-III, Addenbrooke’s Cognitive Examination; AES-C, Apathy Evaluation Scale-clinician version; FNAT, Face Name Associations Task; RAVLT, Rey Auditory Verbal Learning Test; MDRS, Mattis Dementia Rating Scale; QoL, quality of life; AM, associative memory; PVLT, 12-Word Philadelphia Verbal Learning Test; BDI, Beck Depression Inventory; PSQI, Pittsburgh Sleep Quality Index; CDR-SB, Clinical Dementia Rating-sum of boxes; EEG, electroencephalography; FDG-PET, fluorodeoxyglucose-positron emission tomography; MRI, magnetic resonance imaging; VF, verbal fluencies.

While these studies suggest potential cognitive benefits of rTMS in AD, it is worth noting that the effects appear to be modest, and not all studies have reported positive results. Moreover, the optimal parameters for rTMS in AD, including the best cortical target, stimulation frequency, and duration of treatment, remain to be determined.

A recent meta-analysis supports the beneficial effects of rTMS on general cognitive function in patients with AD, with improvements seen immediately and maintained in the long term [50]. High-frequency rTMS, particularly when targeted at the left DLPFC, is associated with superior cognitive outcomes compared to sham rTMS. However, no significant effects were observed on attention, executive, language, and memory functions, emphasizing the need for early rTMS intervention in AD to potentially maximize cognitive benefits [50].

Transcranial direct current stimulation (tDCS)

tDCS is a non-invasive brain stimulation technique that has emerged as a potential therapeutic tool for AD. tDCS applies a low-intensity, continuous electric current to the scalp via two electrodes, an anode and a cathode, creating an electric field that can modulate the resting membrane potential of neurons [51]. The direction of the modulation depends on the polarity of the stimulation: anodal tDCS typically increases cortical excitability, while cathodal tDCS usually decreases it (see Fig. 1).

The interest in using tDCS for AD stems from the premise that by modulating the neural activity of specific cortical regions, it might be possible to enhance cognitive functions and potentially slow down disease progression. In this view, tDCS may provide a comprehensive intervention strategy for AD, engaging with multiple neuronal mechanisms that are typically disrupted in this neurodegenerative disorder. tDCS’s role in modulating cortical plasticity is pivotal, as it offers potential for therapeutic intervention by influencing neuronal firing rates, enhancing synaptic plasticity, and stimulating structural and functional reorganization within the brain. This could have meaningful implications for counteracting the synaptic disruptions and reduced cortical plasticity often seen in AD and may lead to the restoration of compromised cognitive functions. Alongside cortical plasticity, tDCS also serves as a modulator of neural connectivity, a crucial factor given the impaired connectivity observed in AD. By altering the resting membrane potential of neurons, tDCS can fine-tune the functional links between various brain regions, influencing the flow of neural information and restoring overall network connectivity. This capacity to impact neuronal excitability could potentially counteract the cognitive deficits arising from disrupted connectivity in AD and mitigate memory loss by reinstating the coherence among different brain regions [28]. In addition, tDCS exerts an influence on cortical reactivity by modulating the excitability of cortical neurons. This enhanced responsiveness can potentially reactivate less functional brain areas affected by AD, serving as a catalyst for cognitive function improvement and symptom reduction. Lastly, tDCS has been shown to influence neurotransmission, the fundamental process underlying communication between neurons. This influence is particularly relevant for neurotransmitters such as glutamate and GABA. Glutamate, an excitatory neurotransmitter, plays a crucial role in synaptic plasticity and memory formation. On the other hand, GABA, an inhibitory neurotransmitter, is essential for regulating neuronal excitability and maintaining the balance between excitation and inhibition within the brain. In AD, there is often a disturbance in the balance between these two neurotransmitters, leading to an overexcitation of neural circuits that can contribute to neuronal damage. By delivering a low-intensity current, tDCS can modulate the release of these neurotransmitters, potentially restoring the disturbed excitatory/inhibitory balance.

Preclinical animal studies have shown promising results with tDCS, which has been linked with improved learning and memory and a reduction in amyloid-beta plaque load, potentially through the enhancement of long-term potentiation and the modulation of proteins involved in synaptic plasticity [52, 53]. Clinical trials have built upon this foundation with mixed but promising results [21].

One of the pioneering studies investigating the application of tDCS in AD was conducted by Ferrucci et al. in 2008. The researchers targeted the left DLPFC and observed significant enhancements in working memory tasks following anodal tDCS, hinting at the potential utility of tDCS in managing cognitive impairments associated with AD [54].

Building on this, a randomized, double-blind, sham-controlled trial by Boggio et al. applied anodal tDCS over the left DLPFC and cathodal tDCS over the right DLPFC for five consecutive days in patients with AD. They demonstrated that active tDCS resulted in significant improvements in visual recognition memory performance [55].

Cotelli et al. expanded the investigation into the effects of tDCS on memory functions in AD. They found that anodal tDCS over the left DLPFC administered during face-name associations memory training for 2 weeks led to improved recognition which was still significant at 12 weeks, highlighting the potential of tDCS to augment specific memory processes [56]. Furthermore, Suemoto et al. reported a decrease in apathy in patients with moderate AD following left DLPFC stimulation, emphasizing the potential of tDCS to mitigate neuropsychiatric symptoms in AD [57].

In a more substantial study involving 34 patients with AD, Khedr et al. administered either anodal tDCS over the left DLPFC or sham stimulation for 10 days. The active tDCS group demonstrated significant improvements in the MMSE and instrumental activities of daily living scores. Notably, these benefits persisted for two months post-treatment, suggesting tDCS may have long-lasting effects [58].

A subsequent double-blind, placebo-controlled trial by the same group but targeting the left and right temporoparietal region provided additional support for the therapeutic potential of tDCS in AD, showing cognitive enhancements following tDCS treatment [59].

Recently, Gangemi et al. conducted two randomized studies investigating the effects of short- and long-term neurostimulation via tDCS in patients with AD. They found that stimulation over the left frontal and temporal cortex improved global cognitive functioning, with long-term tDCS offering more persistent benefits. This evidence suggests that tDCS could have a cumulative effect, with extended stimulation leading to sustained cognitive improvements [60].

Another interesting approach has been adopted by Hu et al. In a randomized trial of 84 patients with AD, the simultaneous application of rTMS and tDCS over the bilateral angular gyrus demonstrated notable efficacy in addressing neuropsychiatric symptoms. At weeks 4 and 12, the rTMS-tDCS group showed greater improvement in neuropsychiatric symptoms, as measured by the Neuropsychiatric Inventory (NPI), compared to those receiving single-tDCS and sham stimulation, with a trend towards better outcomes than single-rTMS. Furthermore, rTMS-tDCS led to improvements in cognitive function (MMSE) and sleep quality (Pittsburgh Sleep Quality Index), with these improvements associated with the NPI changes. The safety profile of the combined rTMS-tDCS approach was also deemed satisfactory. This suggests that combined rTMS-tDCS could be an effective, safe strategy for managing AD-related neuropsychiatric symptoms and cognitive decline [61].

For an overview of published studies employing tDCS in AD, see Table 3.

Table 3

Studies employing transcranial direct current stimulation (tDCS) in Alzheimer’s disease treatment

Study	N. of patients	Target area	Disease stage	Experimental design	Stimulation parameters	Main outcomes
Ferrucci et al. 2008 [54]	10	TC, PC	AD [83,85, 83,85]	Randomized, double-blind, sham-controlled	Anodal 1.5 mA×15 min×1 session	Word recognition task
Boggio et al. 2009 [125]	10	TC	Mild-moderate AD	Randomized, double-blind, sham-controlled	Anodal 2 mA×30 min×1 session	Stroop, Digit Span, VRM
Boggio et al. 2012 [55]	15	TC	AD [83,85, 83,85]	Randomized, double-blind, sham-controlled	Anodal 2 mA×30 min×5 sessions (5 days)	ADAS-cog, MMSE, VRM, VAT
Cotelli et al. 2014 [56]	36	L DLPFC	AD [83]	Randomized, double-blind, sham-controlled	Anodal 2 mA×25 min×10 sessions (2 weeks)	FNAT, MMSE, ADL, NPI, other
Khedr et al. 2014 [58]	34	L DLPFC	AD [83]	Randomized, double-blind, sham-controlled	Anodal/Cathodal 2 mA×25 min×10 sessions (10 days)	MMSE, IQ-WAIS, ERP, TMS
Suemoto et al. 2014 [57]	40	L DLPFC	AD [83]	Randomized, double-blind, sham-controlled	Anodal 2 mA×20 min×6 sessions (2 weeks)	MMSE, Apathy, NPI, ADAS-cog, other
Bystad et al. 2016 [126]	26	L TC	AD [105]	Randomized, double-blind, sham-controlled	Anodal 2 mA×30 min×60 sessions (10 days)	CVLT, MMSE, TMT
Roncero et al. 2017 [127]	10	Inferior TPC	AD [105]	Randomized, double-blind, sham-controlled	Anodal 2 mA×30 min×10 sessions (10 days)	Memory
Khedr et al. 2019 [59]	46	L/R TPC	Mild-moderate AD [105]	Randomized, double-blind, sham-controlled	Anodal 2 mA×20 min×10 sessions (2 weeks)	MMSE, CDT, MoCA, CDS
Im et al. 2019 [128]	18	L DLPFC	Mild AD [83,85, 83,85]	Randomized, double-blind, sham-controlled	Anodal 2 mA×30 min×180 sessions (6 months)	MMSE, FDG-PET, other
Cespón et al. 2019 [129]	12	L DLPFC	AD [83]	Randomized, double-blind, sham-controlled	Anodal/Cathodal 2 mA×25 min×1 session	Reaction times, ERP
Inagawa et al. 2019 [130]	20	L DLPFC	Mild-moderate AD [115]	Randomized, double-blind, sham-controlled	Anodal 2 mA×20 min×10 sessions (5 days)	ADAS-cog, MMSE, FAB
Liu et al. 2019 [131]	17	L/R FC, L/R TC	MCI and mild AD [115]	Randomized, double-blind, sham-controlled	Anodal 2 mA×20 min×1 session	ADAS-cog, MOCA
Rasmussen et al. 2021 [132]	19	L DLPFC	AD [105]	Randomized, double-blind, sham-controlled	Anodal 2 mA×20 min×3 sessions (1 day)	MMSE, MRI
Gangemi et al. 2021 [60]	44	L FC, L TC	Mild AD	Randomized, double-blind, sham-controlled	Anodal 2 mA×20 min×80 sessions (8 months)	MMSE, MODA
Smirni et al. 2021 [133]	40	L/R DLFPC	Mild AD [105]	Open-label	Anodal 1 mA×20 min×1 session	VF
Andrade et al. 2022 [134]	36	L/R DLFC, Bro, Wer, L/R PC	Mild-moderate AD [105]	Randomized, double-blind, sham-controlled	Anodal 2 mA×30 min×24 sessions (two months)	ADAS-cog, EEG,

TC, temporal cortex; PC, parietal cortex; TPC, temporo-parietal cortex; FC, frontal cortex; Bro, Broca’s area; Wer, Wernicke’s area; VRM, visual recognition memory; VAT, visual attention task; FNAT, Face-Name Association Task; MMSE, Mini-Mental State Examination; ADL, activities of daily living; NPI, Neuropsychiatric Inventory; WAIS, Wechsler Adult Intelligence Subscales; ERP, event related potentials; TMS, transcranial magnetic stimulation; CVLT, California Verbal Learning Test; TMT, Trail Making Test; CDT, Clock drawing test; MoCA, Montreal Cognitive Assessment; CDS, Cornell Depression Scale; FDG-PET, fluorodeoxyglucose-positron emission tomography; FAB, frontal assessment battery; MODA, Milan Overall Dementia Assessment.

Despite these encouraging results, it should be noted that not all studies have found positive effects of tDCS in AD, and the results have been quite variable. This variability might be due to differences in stimulation parameters, targeted brain regions, and patient characteristics. Moreover, the optimal parameters for tDCS in AD, including the most effective electrode montage, stimulation intensity, and duration of treatment, are still unknown.

A recent meta-analysis found no significant difference in the immediate or long-term effects of tDCS on general cognitive function, attention, language, or memory functions between the tDCS and sham groups [50]. However, previous meta-analyses have reported significant improvements in general cognitive function in mild and moderate AD with tDCS treatment [62, 63]. High heterogeneity was observed among the included studies, with meta-regression suggesting that the intensity of stimulation could be a significant source of this variability [50].

Transcranial alternate current stimulation (tACS)

tACS is a non-invasive brain stimulation technique that has the potential to modulate cortical activity and cognitive functions. Unlike tDCS, which applies a constant electric current to the scalp, tACS delivers a sinusoidal current that alternates in polarity at a specific frequency. This oscillating current can interact with the natural neural oscillations in the brain, potentially entraining or disrupting these rhythms depending on the frequency and phase of the applied current [64] (see Fig. 1).

The interest in using tACS for AD stems from the observation that AD is associated with disruptions in neural oscillations, particularly in the theta and gamma frequency bands, which are crucial for cognitive functions such as memory and attention [65 –67]. Additionally, animal studies have demonstrated that entrainment at gamma frequencies, achieved via optogenetic or sensory (visual, auditory) stimulation, can enhance cognitive performance and mitigate the pathological markers of the disease [68 –70]. Preclinical studies in mouse models of AD have shown that gamma tACS may affect the long-lasting enhancement of synaptic transmission [71]. Therefore, the hypothesis is that by modulating these oscillations using tACS, it might be possible to enhance cognitive functions and potentially slow down disease progression.

However, it should be noted that, as of now, the application of tACS in AD is still in its early stages, and the number of clinical trials employing tACS in AD is relatively small compared to other brain stimulation techniques like rTMS and tDCS.

Bréchet et al. introduced a novel approach of home-based tACS targeted at the left temporoparietal cortex, administered by caregivers and remotely monitored by a study team. This approach aimed at modulating specific brain oscillations associated with memory deficits. Preliminary data from two patients with AD-related dementia demonstrated the feasibility and safety of this intervention. This initiative paved the way for more comprehensive randomized controlled trials, potentially revolutionizing the management of memory dysfunction in AD [72].

In a study by Benussi et al., the effects of tACS at gamma frequency (γ-tACS) on memory and cholinergic transmission were investigated in patients with mild cognitive impairment due to AD (MCI-AD). Notably, the γ-tACS was applied over Pz for 60 minutes, an area overlying the medial parietal cortex and the precuneus. The study revealed significant improvements in episodic memory and increased cholinergic transmission immediately after γ-tACS compared to sham tACS. These findings support the role of γ-tACS in improving memory performance and restoring intracortical connectivity measures of cholinergic neurotransmission in patients with MCI-AD [73].

Subsequently, Benussi et al. extended their previous work to assess the effects of 60 minutes γ-tACS applied over the precuneus in 60 patients with early-stage AD. The study found significant improvements in episodic memory and increased cholinergic transmission immediately after γ-tACS. Interestingly, the APOE genotype and baseline cognitive impairment were identified as the best predictors of response to γ-tACS. Moreover, gamma oscillatory activity, as evaluated with EEG, was observed to increase in posterior regions following tACS compared to sham stimulation. This study highlighted the potential of γ-tACS to restore memory performance and cholinergic transmission, with responsiveness dependent on genetic factors and disease stage [74].

Sprugnoli et al. examined the impact of gamma band tACS on cortical perfusion in 15 patients with mild to moderate AD, with target areas individualized according to amyloid PET imaging. A significant increase in blood perfusion in bilateral temporal lobes, measured by arterial spin labeling MRI, was observed post-intervention, correlating with improvements in episodic memory and changes in gamma band spectral power [75].

Lastly, Dhaynaut et al. reported an increase in gamma spectral power on EEG and a significant decrease in phosphorylated Tau burden following tACS treatment, primarily in the targeted left and right temporal lobe regions. However, the impact on amyloid-beta and microglia activation was inconclusive. Despite these promising results, the study emphasized the need for longer interventions and placebo control conditions to fully evaluate the potential of tACS in targeting and engaging with specific biomarkers associated with AD [76].

For an overview of published studies employing tACS in AD, see Table 4.

Table 4

Studies employing transcranial alternate current stimulation (tACS) in Alzheimer’s disease treatment

Study	N. of patients	Target area	Disease stage	Experimental design	Stimulation parameters	Main outcomes
Benussi et al. 2021 [73]	20	Precuneus	MCI [107] with biomarkers	Randomized, double-blind, sham-controlled	40 Hz, 3 mA×60 min×1 session	RAVLT, FNAT, TMS
Bréchet et al. 2021 [72]	2	L TPC	AD with biomarkers	Open-label	40 Hz, 2 mA×25 min×70 sessions (14 weeks)	EEG, MoCA, Memory index
Sprugnoli et al. 2021 [75]	15	Individualized on amyloid PET	Mild-moderate AD	Open-label	40 Hz, 2 mA×60 min×10 sessions (2 weeks) or 20 sessions (4 weeks)	ASL-MRI, ADAS-cog, MMSE, EEG
Dhaynaut et al. 2022 [76]	4	L/R TC	Mild-moderate AD with biomarkers	Open-label	40 Hz, 2 mA×60 min×20 sessions (4 weeks)	Tau/amyloid/microglia-PET, other
Benussi et al. 2022 [74]	60	Precuneus	MCI and mild AD [121] with biomarkers	Randomized, double-blind, sham-controlled	40 Hz, 3 mA×60 min×1 session	RAVLT, FNAT, TMS, EEG, genetics

L, left; TPC, temporo-parietal cortex; TC, temporal cortex; RAVL, Rey Auditory Verbal Learning Test; FNAT, Face-Name Associations Task; TMS, transcranial magnetic stimulation; EEG, electroencephalography; MoCA, Montreal Cognitive Assessment; ASL-MRI, arterial spin labelling magnetic resonance imaging; ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale.

Despite these promising results, it is important to note that the number of studies investigating the effects of tACS in AD is still small, and larger, well-controlled trials are needed to confirm these preliminary findings. While initial findings are encouraging, further research is needed to optimize the stimulation parameters, determine the long-term safety and efficacy of tACS, and understand its mechanisms of action.

CONCLUSIONS

The recent surge of therapeutic trials for AD has brought an array of innovative neuromodulatory techniques to the forefront, promising to revolutionize our understanding and treatment of this debilitating disease. A wide spectrum of both invasive and non-invasive brain stimulation techniques, such as DBS, rTMS, tDCS, and tACS, have been explored, resulting in varying degrees of success.

DBS, a form of invasive neuromodulation, has shown promise in preliminary studies, particularly targeting the fornix, a region integral to memory circuitry. However, the invasiveness and high costs associated with DBS limit its widespread use and warrant further investigation into its long-term effects and optimal stimulation parameters.

Non-invasive techniques such as rTMS, tDCS, and tACS have exhibited notable effects on cognitive and neuropsychiatric symptoms associated with AD. rTMS and tDCS has both shown a capacity to enhance cognitive function and reduce neuropsychiatric symptoms in patients with AD. Recent studies on tACS have provided preliminary evidence of its potential to modulate brain oscillations associated with memory deficits in AD. Despite the initial promising results, the optimal parameters for these stimulation techniques, including frequency, intensity, and duration of treatment, remain unknown. The variability in outcomes across studies necessitates further, larger-scale investigations.

In the context of brain stimulation, it is essential to recognize the promising potential of network-based and individualized stimulation strategies in the treatment of AD. Network-based stimulation builds on the understanding that our brain’s functionality is not merely the product of isolated regions working independently, but rather the result of intricate networks of interconnected regions working collaboratively. This perspective is particularly pertinent to the context of AD, a condition that does not confine its impact to a single brain area but instead affects a complex, interconnected network of structures. Such an approach could involve stimulation techniques that specifically target crucial brain networks implicated in AD, such as the DMN, salience network, or central executive network. By modulating the activity across these pivotal networks, rather than focusing on isolated regions, we could potentially intervene in a more targeted and effective manner. Research has shown that AD affects specific networks, and thus, interventions targeting these networks could be more beneficial [48, 76].

Parallel to the network-based approach, we should also consider the potential of individualized stimulation strategies. Given the heterogeneity of AD, in terms of disease progression, clinical manifestation, and response to treatment, a one-size-fits-all approach may not be optimal. Individualized stimulation would involve customizing the stimulation parameters, such as the targeted location, frequency, and intensity, based on each patient’s specific characteristics, disease stage, and other relevant factors. This could involve using imaging or genetic biomarkers to guide the choice of stimulation target or adjusting stimulation parameters based on the individual’s response to treatment [75].

A particularly exciting frontier is the convergence of brain stimulation with cognitive training or pharmacological treatments. The premise here is that combining treatments could potentially stimulate complementary mechanisms and enhance brain plasticity. This combined approach could capitalize on the strengths of each intervention, with brain stimulation targeting specific neural circuits and cognitive training or pharmacotherapy further facilitating neural adaptability. Future research should focus on identifying the most effective combinations of these modalities to optimize therapeutic outcomes. Furthermore, the combination of non-invasive brain stimulation approaches may present novel opportunities in AD treatment. Combining different modalities, such as rTMS, tDCS, and tACS, could potentially enhance therapeutic effects by targeting different neural mechanisms or circuits simultaneously or sequentially. For instance, one modality could be used to prime the brain for subsequent treatment with another, or different modalities could be employed to target complementary aspects of neural function. While these combined approaches show promise, more research is needed to establish optimal protocols and assess their safety and efficacy.

Home-based remotely supervised treatments also offer a significant leap forward. With the advent of portable brain stimulation devices and digital health technologies, home-based treatments could provide a practical and scalable solution to alleviate the burden of AD. Notably, such a treatment approach could enhance patient accessibility, adherence, and comfort while reducing healthcare costs. Preliminary studies have demonstrated the feasibility and safety of home-based tDCS and tACS, setting the stage for larger, controlled trials [77, 78].

In light of these developments, it is crucial to remember that we are still in the early stages of understanding how best to apply these stimulation techniques in the context of AD. A host of questions remain, such as how to individualize treatments based on patient characteristics, disease stage, or genetic markers, and how to sustain and maximize the benefits of brain stimulation.

Moreover, as we delve deeper into the realm of brain stimulation, it is important to keep an eye out for novel stimulation techniques that may emerge. For example, techniques that could target deeper brain structures non-invasively, such as temporal interference stimulation [79], or those that could provide real-time feedback and adapt the stimulation parameters based on the patient’s brain activity [80], could further enhance the effectiveness of brain stimulation in treating AD.

An integral point of consideration when evaluating and comparing the studies in question is the inherent variability arising not just from differing inclusion criteria, but also the wide range of treatment durations. The studies range from single-session interventions to those extending over six months, making direct comparison of efficacy challenging. Similarly, the discrepancy in participant selection and diagnostic verification methods across studies, with biomarker-supported diagnosis being incorporated only sparingly, can introduce significant heterogeneity in results. This variability could potentially skew interpretations and cross-study comparisons, highlighting the importance of implementing standardized selection processes and comprehensive diagnostic criteria in future investigations. Emphasizing longitudinal consistency in treatment duration across studies would also be advantageous for creating a more level playing field for efficacy comparisons. Moreover, promoting the incorporation of biomarker-supported diagnoses could provide a solid foundation to study findings, enhancing confidence in results and facilitating more meaningful cross-study comparisons.

Finally, the ethical implications of using brain stimulation in a vulnerable population such as in patients with AD should not be overlooked. As we strive to push the boundaries of therapeutic possibilities, it is essential to ensure that the benefits of these interventions outweigh the possible risks.

In summary, the landscape of brain stimulation for AD is evolving rapidly, fueled by technological advancements and our growing understanding of the disease pathophysiology. While the results so far are promising, it is important to approach them with cautious optimism. The ultimate goal remains to deliver safe, effective, and accessible treatments for patients with AD that can significantly improve their quality of life and slow the progression of this devastating disease.

As we continue to explore the potential of these brain stimulation techniques, there’s a strong need for well-designed, large-scale clinical trials that can systematically evaluate their efficacy and safety, providing robust evidence to guide clinical practice. Such trials should also consider the heterogeneity of AD, stratifying patients based on factors such as disease stage, genetic profile, and co-existing neuropsychiatric symptoms. This approach will help us uncover the full therapeutic potential of these techniques, identify the most responsive patient subgroups, and tailor the treatment strategies to meet individual patient needs.

In conclusion, the therapeutic trials of brain stimulation in AD are paving the way towards more effective, personalized, and comprehensive treatment strategies. Despite the challenges that lie ahead, the progress made so far is promising, and the future of AD treatment seems brighter than ever. We are now at a critical juncture where technological advancements, deepened understanding of AD pathophysiology, and innovative treatment modalities are converging, offering new hope for millions of patients with AD worldwide.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

AB was partially supported by Fondazione Cariplo (grant n° 2021-1516), and by the Fondation pour la Recherche sur Alzheimer.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

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