Etiology and Clinical Significance of Network Hyperexcitability in Alzheimer’s Disease: Unanswered Questions and Next Steps

Abstract

Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer’s disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed “subclinical epileptiform activity” (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention.

Keywords

Alzheimer’s disease amyloid-β epilepsy hyperexcitability interictal epileptiform discharge seizure tau

INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, causing 60-80%of dementia in the United States [1]. It is characterized by the pathological hallmarks of extracellular amyloid-β (Aβ) plaques and intracellular, abnormally hyperphosphorylated, tau neurofibrillary tangles [2]. Animal models suggest that episodic memory impairment, a characteristic dysfunction in early AD, is due to transsynaptic progression of neuronal network dysfunction induced by tau and Aβ [3]. This network dysfunction may have predictable neurophysiological correlates. Neuronal hyperexcitability in AD is being investigated as a modifiable step in the pathogenesis of cognitive impairment [4]. Hyperexcitability can exist subtly in the form of neuronal hyperactivity and functional network disinhibition, measurable by neurophysiologic spectral changes seen in humans and in rodent models of Aβ dysfunction, or more explicitly as seizures or interictal epileptiform discharges [5 –8]. Focal or diffuse slow activity (shift into lower frequency bands) or changes in neural synchrony may also be a marker of aberrant network activity in AD [9].

Anti-seizure medications (ASMs) are being investigated for cognitive symptom modification in AD [10]. A recent phase II clinical trial of patients with AD suggested improvements, in post-hoc analyses, in spatial memory and executive function with low dose levetiracetam in AD patients with electroencephalographic (EEG) or magnetoencephalographic (MEG) evidence of interictal epileptiform discharges (IEDs), though the majority of patients did not have known clinical seizures [4]. There could, therefore, be utility in screening AD patients for the presence of these discharges. Although anti-amyloid therapies have disease-modifying potential, safety and efficacy of these drugs require further investigation [11]. Continued evaluation of disease mechanisms at all stages of the causal chain leading to cognitive dysfunction in AD remains an important strategy for the design of novel therapies. An improved understanding the pathogenesis of seizures and IEDs, and their relationship to cognitive and behavioral symptoms, will suggest therapeutic targets for symptom relief and ultimately disease modification. This may be relevant to certain AD patients with an “epileptiform phenotype” or ultimately to all patients with AD, depending on mechanisms uncovered [12].

EVIDENCE OF HYPEREXCITABILITY IN AD

While seizures are the clinically evident expression of hyperexcitability, subclinical epileptiform activity (SEA), including IEDs, are beginning to be better characterized in AD patients. There is a range of prevalence estimates of SEA in AD reported in the literature, likely related to small sample sizes and variable sample characteristics [13]. Vossel et al. (2016) [14] prospectively enrolled 33 patients with early-onset AD (mean age 62 years) and 19 controls and found that subclinical epileptiform activity (activity excluding clinical seizures) was present in 42.4%of AD patients, which significantly differed from controls. In a study of 54 AD patients with late-onset AD (mean age 75.5 years), subclinical epileptiform activity was present in 54%[15]. By contrast, Lam et al. (2020) [13] found that in 41 patients with AD without known seizures (mean age 76.6 years), SEA were seen in 22%.

Seizures

In comparison to healthy controls, patients with AD have a 6-10x higher rate of developing seizures [16, 17]. Seizure timing in the course of AD is variable. They are common in early onset AD (EOAD), and in 198 patients with AD onset prior to 65 years of age, 45%had seizures [18]. By contrast, in another series of > 7,000 patients with AD, those with disease duration longer than 3 years had a higher risk of developing seizures [19]. In a cohort of 236 patients, the incidence ratio for seizures was 87 : 3 when comparing the youngest with older patients with AD [20].

Though focal-onset seizures, particularly from the temporal lobe, are more common in AD, generalized-onset seizures, including myoclonic seizures and generalized-onset tonic-clonic seizures, have been reported [5]. LOMEDs (late-onset myoclonic epilepsy in Down’s syndrome) has been identified in patients with Down’s syndrome and AD. These seizures are associated with generalized spike-and-wave or polyspike-and-wave discharges as well as worsening cognition, with some features similar to progressive myoclonic epilepsy [21]. Semiologically, focal-onset seizures in AD/mild cognitive impairment (MCI) patients resemble typical temporal lobe seizures, with bland manifestations that can be difficult for observers to identify. Symptoms in these patients suggest involvement of mesial temporal and interconnected structures, with psychic phenomena, speech arrest, autonomic symptoms, déjà vu/jamais vu and/or sensory symptoms, with or without impaired awareness [5].

Unexplained phenomena or spells of altered awareness

Wandering and ill-defined, at times prolonged, spells of altered cognition are reported frequently in patients with AD. These spells tend to be stereotyped and recurrent and can have both positive and negative symptomatology [22]. Transient focal neurological events called amyloid “spells” in cerebral amyloid angiopathy, a condition which is characterized by amyloid deposits in blood vessels, are possibly related [23]. The pathologic findings of amyloid angiopathy often occur in AD as well [24]. Cerebral amyloid angiopathy is associated with blood-brain barrier (BBB) dysfunction [25]. Given the relationship between that phenomenon and hyperexcitability (referenced further below), these events may reflect overall network hyperexcitability even if they are not associated with ictal discharges. However, this is controversial, and they may instead be related to cortical spreading depression secondary to superficial siderosis and/or cortical microbleeds [26]. The efficacy of empiric treatment with anti-seizure medications for spells of altered cognition has not been assessed in treatment trials.

IEDs

IEDs (consisting of spikes and sharp waves) are typically found in patients with epilepsy and have been demonstrated in AD [27]. They are defined as paroxysmal sharp waveforms that disrupt the EEG background, lasting 20-200 ms in duration, often with slow waves afterwards. Depending on their cortical location, they are more or less likely to be associated with epilepsy. In the temporal region, they are more likely to be associated with focal seizures than to be incidental [28]. There is evidence that they had clinical consequences in mouse models of AD, but whether they have clinical consequences in humans is debated. In a series of patients with AD as compared to healthy control participants, specific features of IEDs correlated with likelihood of having seizures (i.e., frequent discharges, more convincing morphology, occurrence during wakefulness and REM sleep) [13].

MECHANISMS OF HYPEREXCITABILITY IN AD

Excitation-inhibition imbalance as the main mechanism underlying hyperexcitability is theorized to contribute to AD pathogenesis early, perhaps years prior to the onset of cognitive symptoms, and we summarize contributors below. Please see a recent review for an excellent figural overview of the drivers behind hyperexcitability in AD [29]. Multiple mouse models of AD have demonstrated neuronal and astrocytic hyperactivity, particularly close to Aβ plaques [30, 31]. Both excitotoxicity and decreased inhibition associated with AD pathophysiology—Aβ and tau, have been implicated in the development of hyperexcitability [32, 33].

Aβ

Abnormal Aβ₄₂ deposition leads to plaque formation in AD and may contribute to the dementia phenotype by causing synaptic dysfunction rather than direct neurotoxicity [34]. Transgenic mice with overexpression of human amyloid precursor protein (hAPP) and in vitro models of different Aβ assembly states have delineated an effect of Aβ₄₂ on neural networks [35]. Soluble Aβ directly impairs synaptic plasticity (decreasing long-term potentiation and increasing long-term depression as well as reducing dendritic spines) and memory in rodent models [36]. Mechanisms involving Aβ-induced disruption of neural network activity include changes in synaptic transmission and excitatory/inhibitory neurotransmitter function, as well as intrinsic neuronal properties. Hyperexcitability precedes the development of synaptic dysfunction [37].

Soluble Aβ oligomers accumulate intracellularly early in the entorhinal cortex and hippocampus [38]. They may lead to changes in intrinsic neural excitability as measured by current-clamp recording of basal cholinergic forebrain neurons, which occurs in mouse models prior to Aβ plaque formation [39, 40]. Fibrillar Aβ can also lead to pyramidal cell depolarization and increased excitability in mouse models of AD, leading to seizures [30]. Oligomeric Aβ is specifically demonstrated to increase global synaptic transmission, excitability, and neural synchrony by protein kinase C-induced post-synaptic potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamatergic currents [41]. Inhibiting degradation of Aβ results in neuronal hyperactivity [42]. Oligomeric Aβ blocks glutamate uptake and promotes synaptic long-term depression [43]. Increased Aβ also affects inhibitory pathways by downregulating GABA inhibitory interneuron activity and loss of these interneurons, which in hAPP mice may be associated with reduced gamma oscillatory activity, suggesting another physiologic substrate for hyperexcitability and/or seizure activity in AD [44, 45]. Soluble AβPP can directly bind to GABA-B receptors, modulating GABAergic transmission [46]. Effects on synaptic transmission are dose dependent: with small endogenous increases in Aβ, presynaptic facilitation leading to excitotoxicity can occur. Larger increases in Aβ lead to synaptic depression, with optimal synaptic functioning occurring at intermediate levels [47].

Aβ levels are closely linked to synapse loss, the best predictor of cognitive deficits in AD, and in vivo, increased synaptic activity is associated with Aβ deposition, again suggesting that hyperexcitability may herald a deleterious neurodegenerative cascade [48, 49]. Aβ aggregates (dimers and trimers) in vitro decrease density of rat pyramidal neuron spines via an N-methyl-D-aspartate (NMDA)-type glutamate receptor-mediated pathway; the spine density decrease is reversed by specific compounds [50]. Hyperexcitability in the dentate gyrus in a mutant APP mouse model was associated with impaired pattern separation in an early symptomatic stage [51]. In an 5XFAD mouse model, with five familial AD mutations, the earliest Aβ depositions were found in the mammillary bodies, a component of the limbic network with connections to the hippocampus [52]. Patch-clamp recordings of mammillary body neurons demonstrate significant levels of hyperexcitability in the form of spike count. A directed chemogenetic approach was utilized to reduce hyperexcitability at a late stage in mouse development, decreasing mammillary body Aβ, suggesting a bidirectional relationship between hyperexcitability and Aβ levels. Demonstrating a more direct relationship between Aβ and hyperexcitability, an injection of Aβ intracisternally in a 4-aminopyridine model of seizures decreased seizure onset latency and increased the synchronicity of neural network theta activity [53].

Tau

Tau, a microtubular protein, results in neurofibrillary tangles when hyperphosphorylated, and this phenomenon is a pathological substrate of AD. Excessive accumulation of tau is toxic, disrupting synaptic architecture, as assessed by PET imaging of inhibitory and excitatory synapses in a tauopathy mouse model [54]. Tau excess may promote hyperexcitability, as suggested by another tauopathy mouse model demonstrating excitotoxicity mediated by NR2B-containing N-methyl-D-aspartate (NMDA) receptors increasing presynaptic glutamate [55]. Further, wild-type tau levels in a mouse model treated with a tau-focused antisense oligonucleotide correlated with seizure frequency, implying that tau reduction could help treat hyperexcitability [56].

Interaction of Aβ and tau

A synergistic effect on hyperexcitability has been observed between tau and Aβ. In cognitively normal older adults, in vivo tau and Aβ imaging demonstrates a relationship between accumulations of both proteins and medial temporal lobe (MTL) fMRI hyperactivity [57]. A model to link spatiotemporal patterns of Aβ and tau accumulation with AD-related pathologic network changes has been proposed, suggesting that cortical Aβ may induce MTL hyperexcitability, accelerating tau deposition and worsening AD-related structural degeneration [58]. This relationship between tau and Aβ in generating hyperexcitability may be more complex at different stages of disease progression, and not necessarily always synergistic. In mouse model electrophysiologic analyses of the entorhinal cortex, which is affected early by pathologic changes in AD, hAPP expression may increase hyperexcitability, while human tau expression may decrease it [59]. In addition, soluble tau decreases functional network connectivity as assessed by fMRI [60 –62].

Neuroinflammation

While neuroinflammation is a normal response to certain central nervous system (CNS) insults, abnormal neuroinflammation can be promoted by dysfunction in the normal activity of microglia and astrocytes [63]. Astrocytes also contribute to maintenance of the BBB and “leakiness” of this structure can lead to inflammation. Neuropathological changes cause dysfunctional interactions between astrocytes, neurons, and microglia in neurodegenerative disease [64, 65]. Leakage of plasma proteins, particularly fibrinogen, through a compromised BBB may lead them to bind to Aβ, promoting neuroinflammation and neurodegeneration [66]. Neuroinflammation, caused by microglia, astrocytes, impaired endothelial cells, and specific mediators including chemokines, cytokines, and caspases among others, leads to dysfunction of the neurovascular unit, a hallmark of AD pathology [67]. An excitation/inhibition imbalance is affected by glial-mediated synaptic remodeling in neurodegenerative disease [68]. In addition, a link between neuroinflammation and hyperexcitability is seen in epilepsy, with glial dysfunction implicated in epileptogenesis [69]. 41%of 315 patients with refractory temporal lobe epilepsy (TLE) who underwent surgery for seizure control had evidence of diffuse brain inflammation, and hippocampal inflammation [70]. BBB permeability also contributes to seizure frequency and epilepsy progression in TLE [71].

Shared mechanisms of hyperexcitability between temporal lobe epilepsy and AD

TLE, particularly mesial TLE (mTLE) associated with hippocampal sclerosis, overlaps with AD in mechanisms of hyperexcitability. This comparison is of interest given that seizures associated with medication-refractory mTLE can lead to cognitive degeneration [72]. The degree of hippocampal volume loss is similar in both conditions, though it tends to be unilateral in mTLE [73]. In a series of 101 patients with TLE, 10 had amyloid plaques, and the likelihood of plaque presence correlated with age [74]. In 33 patients with TLE, 94%had tau pathology, in some cases characteristic of AD, and the degree of tau burden correlated inversely with verbal learning scores [75].

POSSIBLE CONTRIBUTION OF HYPEREXCITABILITY TO COGNITIVE CHANGES IN HUMANS

In a series of AD and amnestic MCI (aMCI) patients, in 83%seizure onset often coincided with the onset of worsened cognition [5]. Further, earlier onset of cognitive symptoms and worse cognitive and functional performance was associated with a history of seizures in > 20,000 individuals with AD [76]. Ongoing seizure activity is linked to worsening cognitive performance over time [77]. Higher lifetime seizure frequency and uncontrolled seizures in TLE do appear to be correlated with cognitive functioning [78].

There is growing evidence that temporal lobe IEDs seen in patients with epilepsy lead to transient cognitive impairment, and they may also worsen existing neurocognitive deficits [79]. Focal IED suppression improves cognition [80]. Although the prevalence of IEDs in early AD is unclear, in comparison to patients with focal epilepsy, temporal IEDs in patients with dementia more frequently occur without clinically evident seizures [81]. In a sample of 33 patients with AD without a history of seizures, subclinical epileptiform activity was assessed longitudinally over > 3 years [14]. In this study, IEDs were associated with a significantly faster decline in cognition, by Mini-Mental Status Examination, in comparison to patients without them, a finding replicated elsewhere [15].

While the natural history and cognitive consequences of TLE and AD differ, they share pathological substrates (including hippocampal sclerosis and dentate gyrus hyperexcitability), and may have common functional deficits, as assessed by dysfunction in fMRI resting state networks [82]. The similarities between these diseases is relevant to understanding whether suppressing IEDs may improve cognition in one or both.

Overall, the cognitive impact of IEDs in AD deserves further study, as does the question of whether suppressing them would improve cognition or slow the rate of its decline over time. A limitation in studying this phenomenon in elderly patients is that IED morphology becomes less distinct over time [83].

CANDIDATE BIOMARKERS OF HYPEREXCITABILITY

Amyloid and tau pathology on imaging or in cerebrospinal fluid are evidence for AD/aMCI in general, rather than specifically for a hyperexcitable state. Therefore, electrophysiological and imaging markers have utility for defining hyperexcitability, which may occur at different times in the disease course for different patients. Its detection could lead to directed therapies, particularly if its early identification can change the cognitive course in dementia. While structural imaging demonstrates changes in gray and white matter integrity, functional imaging assesses vascular contributions to neural activity. MEG and EEG measure cortical neurophysiological activity.

Neurophysiological measures

Electrophysiological measures, including MEG and EEG, are direct measures of neuronal and synaptic activity, in comparison to functional neuroimaging, which relies on vascular processes to approximate brain activity. Both MEG and EEG capture the synchronized activity of cortical pyramidal neurons. MEG measures the magnetic field, which is perpendicular to the electrical field assessed by EEG [84]; therefore, the studies provide complementary information. The temporal resolution of EEG and MEG is superior to fMRI [85]. Synchronized neural activity measures from EEG and MEG can be used to be infer the network activity of brain circuits and their disturbances in different disease states. Cortical and MTL hyperexcitability as measured by EEG/MEG may be more present early in AD. While greater degree of oscillatory changes in delta-theta and alpha bands is associated with the presence of epileptiform activity in AD patients, the temporal relationship between oscillatory changes and SEA is yet to be determined [86, 87]. Please see Table 1 for a review of candidates for screening neurophysiological measures of hyperexcitability in AD.

Table 1

Neurophysiological screening measures for hyperexcitability in AD patients

Test type	Advantages	Disadvantages/Comments
MEG	- Avoids skull filter and surface distortions	- Insensitive to sources oriented radially to scalp surface
	- May demonstrate, compared to EEG, increased capture of IEDs with different polarity in AD patients with subclinical epileptiform activity	- Requires expensive equipment, including magnetically shielded room, only available at certain centers
	- May need to be shorter in duration than standard EEG, thus may not capture sleep state, which can increase yield of IEDs	- Requires access to specialized technologists
	- Spectral measures are accessible
	- Non-invasive
Standard EEG (19 electrodes, 10-20 system)	- Easily accessible at any epilepsy center	- Possible decreased yield, may require prolonged monitoring
	- Spectral measures are accessible	- Less effective source localization
	- Non-invasive
High-density EEG (64 + electrodes)	- Less expensive than MEG, delivers improved source localization compared to standard EEG	- Provides complementary information to MEG, as it may be sensitive to radially oriented spike sources
	- Sensitive to sources oriented both radially and tangentially to scalp surface
	- Spectral measures are accessible
	- Non-invasive
Invasive EEG (foramen ovale electrodes)	- Reports showing increased yield for IEDs in patients with AD	- Requires neurosurgical intervention for placement
Triggered TMS-EEG/MEG	- Can be obtained on demand without need for prolonged recording for spontaneous IEDs or seizures	- Population norms not well defined for hyperexcitability in AD
		- Requires access to specialized equipment

EEG, electroencephalography; MEG, magnetoencephalography; TMS, transcranial magnetic stimulation; IEDs, interictal epileptiform discharges; AD, Alzheimer’s disease.

Hyperexcitability can be assessed by MEG and by EEG. Lam et al. demonstrated that although the incidence of sub- or pauci-clinical temporal lobe seizures in AD is high, often subclinical seizures may not be discernible on scalp EEG using the standard 10-20 system with 19 electrodes, in part because mesial temporal seizures come from a generator that cannot be directly captured on scalp EEG. Rather, foramen ovale electrodes, which record intracranially, may be needed to appreciate them [88]. In a series of 94 patients above the age of 60 admitted to an epilepsy monitoring unit for longer term recording at a university hospital, epilepsy (typically focal-onset) was identified in 46 patients [89]. In this series, the addition of non-standard electrodes aimed at improving identification of temporal seizure onset, including inferior temporal electrodes and true anterior temporal electrodes (F9/10, T9/10, P9/10, T1/2) improved the yield [90]. In patients with AD, as in patients with epilepsy, a shorter recording, such as a routine EEG, may miss ictal or interictal discharges because of sampling error. Therefore, prolonged EEG recordings have the potential to increase detection [14]. Alternatively, machine learning approaches may be applied to traditional scalp EEG to determine a mesial temporal onset [91]. Recently, a novel machine learning algorithm increased human expert sensitivity of detection for hippocampal epileptiform activity in focal epilepsy, an application that is also relevant in the context of neurodegenerative disease [92].

There are several possible advantages of MEG over EEG. MEG can bypass the filter of the skull and offers improved spatial resolution, and combined MEG/EEG has improved sensitivity to IEDs in AD [14]. By contrast, a MEG system is significantly more expensive and less mobile. It is unclear how increasing spatial sampling by high-density EEG, a scalp electrode system using a minimum of 64 electrodes, compares to MEG in improving sensitivity/yield of subclinical epileptiform activity in AD [93]. Source localization can be performed on both MEG and EEG waveforms to identify the source of the IED, using an individualized head model [94].

Given that IEDs in AD are less frequent than they are in epilepsy, and that trained neurophysiologists are required to detect these IEDs, altered frequency-specific neuronal synchrony has been investigated as a surrogate analytic marker to quantify network hyperexcitability. In comparing 30 AD patients without IEDs, 20 AD patients with IEDs, and 35 age-matched controls, reduction in alpha imaginary coherence and increase in delta–theta imaginary coherence distinguished between AD patients with and without IEDs [87]. This analysis is a step towards establishing standardized quantitative neurophysiologic measures of network dysfunction, related to spectral changes and/or changes in functional connectivity indices. These are necessary to define applicability of similar measures in the clinical space. In a preclinical model of AD, intracranial high-frequency oscillations (HFOs) (between 250 and 500 Hz) were identified intracranially that resembled those in epilepsy models [95]. These represent another candidate biomarker for hyperexcitability, especially as efforts toward refining detection of HFOs on scalp EEG are underway [96].

Alternatively, cortical transcranial magnetic stimulation (TMS), a non-invasive brain stimulation technique, integrated with EEG or MEG, can produce evoked potentials whose characteristics can be measured in healthy or disease states. This technique can help to assess for aberrant network activity in patients with AD as compared to healthy controls and can be assessed and followed over time [97]. In contrast, spontaneous EEG and MEG has the disadvantage that only paroxysmal events (seizures and interictal epileptiform discharges) are detected. TMS measures of motor cortical excitability, such as lower resting motor threshold (which implies increased cortical excitability) have been associated with worse cognitive outcomes [98, 99]. TMS-EEG recordings have also demonstrated regional precuneus hyperexcitability in mild-to-moderate AD relative to age-matched healthy controls [100]. There are also reports of AD- related decreased intermittent theta burst stimulation plasticity, a plasticity protocol that is believed to reflect mechanisms of synaptic long-term potentiation; these deficits are believed to be due to baseline network hyperexcitability [101, 102].

Imaging

Hippocampal sclerosis (HS) is a common finding in TLE. In a series of 169 patients with sporadic AD, evenly split between LOAD/EOAD, 29%of patients with LOAD had HS, compared to 19%with EOAD. HS is characterized by cell loss and gliosis in CA1 and subiculum, which could indicate a chronically hyperexcitable state; however, when associated with aging, it may be a pathologically distinct entity, associated with neurodegenerative protein aggregation [103]. Specifically, HS is seen in association with aging in an AD overlap condition, limbic-predominant age-related TDP-43 encephalopathy, which preferentially affects mesial temporal structures [104]. It is possible for HS to exist in older age, separate from AD pathology, so defining a causal relationship is difficult [105].

Functional neuroimaging has revealed evidence of hyperexcitability and dysfunctional networks in AD, as discussed above. Altered functional connectivity between hippocampus and cortical regions may correlate with episodic memory performance in aMCI patients, and default mode network deactivation with memory tasks has been reported [106, 107]. Hippocampal hyperactivity as assessed by task-based fMRI, when dampened in patients with aMCI by levetiracetam treatment, improved memory performance, even without overt, documented seizure activity [10]. MTL hyperactivity may be a time dependent phenomenon, more evident at an MCI stage, and could thus serve as a biomarker for clinical trials of hyperexcitability [108]. Increased hippocampal activation has been reported during memory tasks early during the disease in apolipoprotein E 4 carriers and patients with aMCI, which is associated with accumulation of amyloid on PET and subsequent cognitive decline [109 –111]. Increased mesial temporal resting-state perfusion has also been reported in arterial spin-labeling imaging [112].

Sildenafil, a phosphodiesterase inhibitor, improves cognitive functioning in AD mouse models. A small pilot study of the effects of sildenafil in patients with AD demonstrated a decrease in MTL fractional amplitude of low frequency fluctuations (a measure of spontaneous fMRI activity) unrelated solely to vascular imaging contributions [113], implying normalization of hyperactivity in patients without known/quantified seizures.

WHAT NEXT? DIAGNOSTIC AND THERAPEUTIC AVENUES

Considerations for neurophysiological screening

Given the high prevalence of subclinical epileptiform activity in AD, a case could be made for screening all patients with biomarker-demonstrated AD for IEDs. However, not all forms of screening are equally accessible (i.e., standard routine EEG is likely accessible in terms of expense and equipment at most or all centers treating AD patients but may have limited sensitivity for IEDs). Deeper clinical phenotyping of neuropsychiatric symptoms in AD patients may identify episodic increases in agitation or sleep disturbances more suggestive of subtle seizures. These may be candidates for more advanced neurophysiological techniques, such as MEG or high-density EEG, or for prolonged standard EEG monitoring in the inpatient or ambulatory setting. Spectral analytic measures, such as changes in neural synchrony and high frequency oscillations discussed in the candidate biomarkers section above, may also play a role. Until reliable and standardized objective measures are defined, continued research into clinically apparent differences between AD patients with and without subclinical epileptiform activity may identify a salient triaging algorithm.

Anti-seizure medications as potential disease-modifying agents

It is yet to be established in a well-powered prospective clinical trial whether ASMs could be disease or symptom-modifying in patients with AD or in the subset of these patients with IEDs. In patients with early AD, MCI, or in pre-symptomatic patients along this spectrum, ASM treatment could be disease-modifying, given that hyperexcitability is part of the pathogenic cascade. Evidence from basic science models suggests that some ASMs can attenuate findings related to hyperexcitability. Lamotrigine reduces AβPP cleavage, rescues deficits in synaptic plasticity, suppresses spike activity and decreases brain inflammatory markers, and improves cognitive phenotypes in APP/PS1 transgenic mice [114, 115].

SV2A-targeting agents (levetiracetam and brivaracetam) have been studied for their role in AD disease modification. SV2A is an integral 12-transmembrane domain glycoprotein expressed in synaptic vesicles and serves as a biomarker of dysfunction in diseases such as AD, where the pathogenesis is related to synaptic dysfunction [116]. In addition, SV2A agents may improve cognitive function. In a mouse model of AD, only levetiracetam, in comparison to ethosuximide, gabapentin, phenytoin, pregabalin, valproic acid, and vigabatrin, suppressed spikes, additionally rescuing cognitive deficits [117]. In another rodent study, brivaracetam, but not an alternative antiepileptic agent, ethosuximide, rescued a cognitive phenotype even though both agents suppressed spikes [118]. In humans, different doses of low-dose levetiracetam improved the cognitive phenotype of aMCI patients on a memory task and ameliorated hippocampal hyperactivity as assessed by high-resolution fMRI [10, 119]. Levetiracetam also modified delta and beta band coherence measures in patients with mild AD [120]. A recent phase II clinical trial suggested improvement, in a post-hoc analysis, in executive function and spatial memory among a small sample of 10 AD patients with known epileptiform activity, which is tantalizingly suggestive of a possible stronger effect in a larger prospective RCT involving this subset of patients [4]. Overall, it appears that among currently available ASMs, there is the strongest evidence for trying lamotrigine and SV2A-targeting agents as possible treatments for hyperexcitability at an early stage of the AD disease cascade.

AD/MCI with clinical seizures

In patients with AD/MCI with epilepsy, tolerability and efficacy may be equally important in ASM choice. Large-scale randomized controlled trials (RCTs) of tolerability and efficacy have not been conducted, but in an RCT of 95 patients evaluating levetiracetam, lamotrigine, and phenobarbital, significant differences were not found in efficacy or tolerability [121]. In a more general context, ASM choice in the elderly should be guided by tolerability. In an RCT of new-onset geriatric epilepsy (the VA Cooperative Trial), when comparing lamotrigine and gabapentin to carbamazepine, while efficacy was similar across the three, both lamotrigine and gabapentin were better tolerated [122]. Another RCT in elderly patients (n = 351) demonstrated similar results, with better tolerability of levetiracetam compared to carbamazepine resulting in higher retention, while seizure freedom rates were similar [123]. Older, enzyme-inducing AEDs, such as valproic acid, carbamazepine, phenytoin, and phenobarbital have unfavorable pharmacokinetic and side-effect profiles for the elderly, so their long-term use in AD is likely not ideal. In particular, lamotrigine, which is a relatively mood- and cognition-neutral ASM option, may be an attractive option for patients with AD with overt seizures [124]. Brivaracetam, which is felt to have fewer behavioral adverse effects than the related levetiracetam (both bind at the presynaptic SV2A receptor, but brivaracetam with greater selectivity), may also be an appealing choice [125].

Neuro-inflammation and BBB dysfunction

Given the hypothesized link between neuro-inflammation and hyperexcitability, therapies that target neuro-inflammation in AD may help to reduce hyperexcitability. Especially in the preclinical setting, anti-inflammatory therapies are being evaluated for the treatment or prevention of AD. In the APP/PS1 mouse model of AD, NLPR3 inflammasome deficiency resulted in decreased deposition of Aβ, as well as an improvement in neurobehavioral disturbances, suggesting a key role of inflammation in AD pathophysiology [126]. Fibrin-targeted immunotherapy directed toward BBB dysfunction may decrease Aβ-related neurotoxicity in model systems [127]. Though results overall have been mixed, in the presymptomatic setting, therapy with non-steroidal anti-inflammatory medications may lead to a significant (67%) risk reduction for AD onset compared to placebo [128, 129].

BBB permeability and involvement of various inflammatory pathways are also involved in the pathogenesis of epilepsy. Anti-inflammatory therapies targeting cyclooxygenase-2, prostanoid pathways, and chemokines are concomitantly being investigated in epilepsy, suggesting a link to hyperexcitability [130, 131]. Identification of biomarkers related to neuroinflammation and/or hyperexcitability will aid in determining the therapeutic window for these treatments in AD.

Tau-based therapeutic strategies

Decreasing tau aggregation or lowering tau levels are mechanisms of interest in therapy for AD. More specifically, tau reduction may be antiepileptic in mouse models of AD, rescuing Aβ related deficits and suggesting an anti-hyperexcitability effect [132, 133]. Truncated forms of tau may specifically disrupt excitotoxicity related to aberrant NMDA receptor activity [134]. In a murine seizure model, antisense oligonucleotide therapy targeted towards tau in the CNS reduced seizures [56], In humans, humanized tau antibodies targeted towards the N-terminal region of the tau protein and the microtubule binding domain are in clinical development [135]. In addition, tau-targeting vaccines are being developed [136].

Neurostimulation

Various forms of neurostimulation have been investigated in AD—invasive (e.g., deep brain stimulation, vagal nerve stimulation) and non-invasive (e.g., transcranial direct or alternating current stimulation or TMS) [137, 138]. Many of these therapies are approved for use in medication-refractory focal epilepsy, while others are being investigated. While the mechanism for its effectiveness in altering cortical hyperexcitability is unknown, neurostimulation may exert long term effects by altering synaptic long-term potentiation and depression in key circuitry disrupted in AD. This could alter the synaptic dysfunction caused by abnormal protein accumulations in AD. In addition, oscillatory brain activity may represent an epiphenomenon of both normal and aberrant brain networks in neurologic and psychiatric disease, which can be influenced by neuromodulation [139].

Pilot studies of TMS to frontal, temporal, and parietal cortical regions (inferior frontal gyrus, Broca’s and Wernicke’s language areas, inferior parietal lobule, and somatosensory association cortex) have been associated with improvements in cognitive task performance [140]. Slow-pulsed transcranial electrical stimulation can be targeted towards suppressing interictal populations in focal epilepsy and spike-suppression is a potential target in AD [141]. Given that sleep fragmentation is a characteristic feature of AD, and Aβ toxicity may interact with sleep deprivation to promote hyperexcitability, state-dependent electrical stimulation therapies could be targeted towards restoring physiologic oscillation patterns in sleep to assess for improvement in hyperexcitability or cognition [142, 143].

CONCLUSIONS

Hyperexcitability, as evidenced by seizures, subclinical epileptiform activity, and functional network alterations is likely an important part of the cascade of AD pathophysiology. Excitation/inhibition imbalance closely associated with AD-related proteins, neurotransmitter dysfunction, and neuroinflammation, may be proximal initiators of network dyssynchrony and dysfunction. While both basic and clinical lines of evidence suggest that modifying hyperexcitability may result in improved cognition, future clinical trials will help determine whether and to what extent treating these phenomena can modify the AD disease course. In addition, establishing when hyperexcitability is clinically relevant for a given patient is a key direction for future research. Currently, long-term electrophysiology recordings with MEG or EEG are required to determine a hyperexcitable state in someone with AD. Quantifiable biomarkers of aberrant network activity to detect the degree of hyperexcitability are needed for the next generation of clinical trials. A multi-pronged treatment approach targeting spike and seizure suppression in patients with MCI and/or early AD with medications, neurostimulation, circadian modulation, anti-inflammatory approaches, and anti-protein (particularly tau) therapies delivered in individualized treatment protocols may represent an ideal approach to treat this devastating disease.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

Dr. Ranasinghe receives grant funding from the National Institutes of Health, Hillblom Foundation, and Alzheimer’s Association. Dr. Rankin receives grant funding from NIH, NSF, and Quest Diagnostics. Dr. Miller receives grant funding from the National Institutes of Health and National Institutes of Aging.

CONFLICT OF INTEREST

Dr. Rankin provides consultation to Eli Lilly. Dr. Miller serves as medical director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Scientific Advisor for the Larry L. Hillblom Foundation and the Buck Institute for Research on Aging; and Scientific Advisory Board Member for the National Institute for Health Research Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia, UK.

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