Introduction
There are an estimated 6.5 million adults aged 65 years and older living with Alzheimer’s dementia (AD) in the United States, and this population is expected to double by 2050. 1 Neuropsychiatric symptoms (NPS) commonly occur over the course of AD and are among the most disabling aspects of the disease. Among NPS, agitation is one of the most prevalent and distressing. Approximately 45% of community-dwelling patients and 53% of nursing home residents exhibit agitated behaviors during the course of AD, and agitation has been observed across mild to severe stages of the disease.Reference Fillit, Aigbogun and Gagnon-Sanschagrin 2 , Reference Halpern, Seare, Tong, Hartry, Olaoye and Aigbogun 3
Agitation is defined by the International Psychogeriatric Association as a syndrome occurring in patients with a cognitive impairment or dementia syndrome; manifesting as excessive motor activity, verbal aggression, or physical aggression associated with emotional distress that is persistent or recurrent for at least 2 weeks; producing behaviors severe enough to produce excess disability; and not being attributable to another disorder.Reference Cummings, Mintzer and Brodaty 4 Agitation is characterized by disruptive or aggressive behaviors such as shouting, cursing loudly, kicking, shoving, and hitting. Agitation may place the patient and the caregiver in danger of harm. Agitation in Alzheimer’s dementia is associated with significant negative patient outcomes, including accelerated disease progression, functional decline, increased institutionalization, and increased mortality.Reference Peters, Schwartz and Han 5 –Reference Jones, Aigbogun, Pike, Berry, Houle and Husbands 7 Additionally, agitation in Alzheimer’s dementia is linked to high caregiver burden and increased health care resource utilization and costs.Reference Cloutier, Gauthier-Loiselle and Gagnon-Sanschagrin 6 –Reference Schein, Houle and Urganus 8
Characterizing the pathophysiology of agitation contributes to understanding the biology of the clinical manifestation of AD and is important for developing potential treatments for agitation in Alzheimer’s dementia. AD is a progressive, neurodegenerative disease characterized by β-amyloid protein (Aβ) plaques, tau protein pathology, and neurodegeneration.Reference Braak, Thal, Ghebremedhin and Del Tredici 9 Accumulating evidence indicates that NPS may be caused by dysfunction within specific neural circuits affected by these pathologies; both structural and functional changes have been identified within key prefrontal and subcortical regions in patients with agitation in Alzheimer’s dementia.Reference Rosenberg, Nowrangi and Lyketsos 10 , Reference Carrarini, Russo and Dono 11 The norepinephrine (NE), serotonin (5-HT), and dopamine (DA) monoamine neurotransmitter systems are important modulators of activity within these brain regions and circuits and are markedly impacted by AD pathological changes.Reference Sara and Bouret 12 –Reference Lanctôt, Herrmann and Mazzotta 16 Dysfunction of the monoamine neurotransmitter systems may contribute to agitation symptoms by disrupting the balance of prefrontal and subcortical activity in circuits required for normal behavioral function. Monoamine neurotransmitter systems may represent key targets for the potential improvement of agitation symptoms in AD.
This review synthesizes research observations into a proposed pathophysiology of agitation in Alzheimer’s dementia, focusing on the potential role of monoamine neurotransmitter systems and related circuits. We first examine how an imbalance between prefrontal and subcortical activity may underlie agitation symptoms in patients with AD. We then explore how monoamine neurotransmitter systems may contribute to dysfunction in these brain regions, examining noradrenergic, serotonergic, and dopaminergic system function in patients with AD and the evidence linking these systems with agitation symptoms. For each system, we synthesize the available evidence to provide a hypothetical model of the neurobiological basis of agitation symptoms. We discuss the potential role of other neurotransmitter systems, including glutamate and γ-aminobutyric acid (GABA), and comment on emerging treatments for agitation in Alzheimer’s dementia and their therapeutic targets.
Prefrontal and Subcortical Dysfunction in Agitation in Alzheimer’s Dementia
Behavior involves a balance between bottom-up reactive responses to stimuli, referred to as emotional drive, and top-down control mechanisms that allow for the regulation of these responses, referred to as executive control.Reference Ray and Zald 17 , Reference Arnsten, Raskind, Taylor and Connor 18 This balance arises from activity within a complex circuitry involving cortical and subcortical brain regions, with the prefrontal cortex (PFC) and amygdala emerging as key nodes of these circuits. The PFC guides many aspects of executive control, including attention and working memory, emotional regulation, and response inhibition, while the amygdala—a key node within the limbic system—plays a central role in the orchestration of emotional responses to sensory input.Reference Ray and Zald 17 –Reference Salzman and Fusi 19 These regions share dense reciprocal connections, with the PFC downregulating reactive processes driven by the amygdala.Reference Ray and Zald 17 , Reference Arnsten, Raskind, Taylor and Connor 18
Disruption of the balance between the PFC and subcortical regions is believed to contribute to NPS, including agitation in Alzheimer’s dementia.Reference Rosenberg, Nowrangi and Lyketsos 10 , Reference Carrarini, Russo and Dono 11 , Reference Ray and Zald 17 Evidence from structural and functional imaging studies as well as postmortem analyses indicates that pathology within specific brain regions, including the PFC and amygdala, may increase the risk of agitation. One study of postmortem brain tissue found that neurofibrillary tangle (NFT) burden in the left orbitofrontal cortex was associated with both agitation and chronic aberrant motor behavior; no relationship with amyloid pathology was observed.Reference Tekin, Mega and Masterman 20 A second study found that the ratio of phosphorylated to total tau within the PFC positively correlated with aggression.Reference Guadagna, Esiri, Williams and Francis 21 Similarly, structural magnetic resonance imaging (MRI) studies of patients with AD have found that agitation, aggression, and aberrant motor behavior were associated with greater gray matter atrophy in the PFC and amygdala.Reference Trzepacz, Yu and Bhamidipati 22 –Reference Jaramillo-Jimenez, Giil and Tovar-Rios 24 Agitation has been linked to pathology in other brain regions involved in emotional processing, including the anterior cingulate cortex and insula.Reference Tekin, Mega and Masterman 20 , Reference Trzepacz, Yu and Bhamidipati 22 , Reference Bruen, McGeown, Shanks and Venneri 25 In a study of patients with AD, cerebrospinal fluid (CSF) levels of both total and phosphorylated tau were associated with greater agitation, while there was no relationship between levels of the 42-amino acid isoform of Aβ protein (Aβ1–42), a biomarker of amyloid pathology, and agitation.Reference Bloniecki, Aarsland, Cummings, Blennow and Freund-Levi 26 Although AD is characterized by both tau and amyloid pathology, these data suggest that tau-mediated pathology may be more influential in the biology of agitation in Alzheimer’s dementia.
Functional magnetic resonance imaging (fMRI) studies have provided further evidence of an imbalance of activity between the PFC and subcortical brain regions in patients with agitation. Fluorodeoxyglucose (FDG) positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies of patients with AD have demonstrated that agitation, aggression, and aberrant motor behavior are associated with hypoperfusion and decreased glucose metabolism within the PFC, as well as within other regions, including the parietal, temporal, and cingulate cortices and insula.Reference Hirono, Mega, Dinov, Mishkin and Cummings 27 –Reference Valotassiou, Sifakis and Tzavara 30 Conversely, agitation is associated with elevated amygdala reactivity to emotional stimuli. An fMRI study showed that patients with AD had a significantly greater amygdala response to both neutral and fearful faces compared to elderly controls and that amygdala responses to familiar neutral faces were positively correlated with severity of agitation and irritability symptoms.Reference Wright, Dickerson, Feczko, Negeira and Williams 31
Collectively, these findings indicate that agitation in Alzheimer’s dementia may arise from an imbalance between executive control, mediated by the PFC, and emotional drive, mediated by subcortical regions, including the amygdala (Figure 1). This imbalance may arise in part from the accumulation of tau pathology and neurodegeneration within key brain regions. A consequence of this pathology is the dysfunction of the monoamine neurotransmitter systems, which modulate the activity of neural circuits throughout the brain and show substantial alterations over the course of AD. The following sections review evidence suggesting that monoamine neurotransmitter system dysfunction may contribute to agitation symptoms.
Figure 1. Hypothesized imbalance between executive control (mediated by prefrontal regions) and emotional drive (provided by subcortical regions, including the amygdala) underlying agitation symptoms in patients with Alzheimer’s dementia. Abbreviations: AMG, amygdala; PFC, prefrontal cortex.
Monoamine System Dysfunction in Agitation in Alzheimer’s Dementia
The noradrenergic, serotonergic, and dopaminergic systems originate primarily in brainstem nuclei and project throughout the brain to modulate the activity of numerous brain regions, including prefrontal and subcortical regions.Reference Sara and Bouret 12 –Reference Serra, D’Amelio and Di Domenico 14 The balance of these systems is dynamic, with reciprocal connections existing among monoaminergic nuclei and their target regions as well as among different monoamine systems.Reference Sara and Bouret 12 , Reference Lanctôt, Herrmann and Mazzotta 16 , Reference Arnsten, Raskind, Taylor and Connor 18
Norepinephrine
The noradrenergic system plays a key role in facilitating emotional responses, including arousal and responses to salient stimuli, the stress response, and fear and anxiety behaviors.Reference Sara and Bouret 12 , Reference Goddard, Ball and Martinez 32 The locus coeruleus (LC) is the primary source of NE in the brain, with LC neurons projecting to key regions, including the PFC and amygdala.Reference Sara and Bouret 12 , Reference Goddard, Ball and Martinez 32 The activity of LC neurons is in turn modulated by reciprocal projections from these target regions, with NE release being driven by the amygdala and regulated by the PFC.Reference Sara and Bouret 12 , Reference Arnsten, Raskind, Taylor and Connor 18 , Reference Goddard, Ball and Martinez 32 Among the neurotransmitter systems examined in this review, a particularly robust body of evidence implicates noradrenergic hyperactivity in the pathophysiology of agitation in Alzheimer’s dementia.
The noradrenergic system is severely impacted over the course of AD. The LC is among the first brain regions impacted in AD, with tau pathology and NFTs observed during the earliest stages of the disease and neuron loss occurring as the disease progresses.Reference Braak, Thal, Ghebremedhin and Del Tredici 9 , Reference Theofilas, Ehrenberg and Dunlop 33 Following the loss of LC neurons, the noradrenergic system undergoes changes that may compensate for neuronal loss and preserve NE signaling based on the following observations.Reference Gannon and Wang 15 First, despite the loss of LC neurons in AD, CSF levels of NE and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) have generally been reported to be unchanged or elevated relative to healthy controls.Reference Elrod, Peskind, DiGiacomo, Brodkin, Veith and Raskind 34 –Reference Henjum, Watne and Godang 37 This may be due to increased NE synthesis by the remaining LC neurons, as supported by the finding of increased expression of tyrosine hydroxylase, the rate-limiting step in NE synthesis, in the LC neurons of patients with AD.Reference Szot, White, Greenup, Leverenz, Peskind and Raskind 38 Second, increased α1-adrenoceptor expression—considered to be a response to decreased NE levels—has been observed in the hippocampus and PFC in patients with AD.Reference Szot, White, Greenup, Leverenz, Peskind and Raskind 38 , Reference Szot, White, Greenup, Leverenz, Peskind and Raskind 39 Third, AD is associated with increased sprouting of dendrites and axonal projections to the hippocampus and PFC by the remaining LC neurons.Reference Szot, White, Greenup, Leverenz, Peskind and Raskind 38 –Reference McMillan, White and Franklin 40
Several lines of evidence from patients with AD indicate that compensatory changes in NE signaling following LC neurodegeneration are associated with agitation symptoms. First, agitation has been associated with greater severity of LC neuron loss. One study reported a negative correlation between number of LC neurons and aggression,Reference Matthews, Chen, Esiri, Keene, Minger and Francis 41 while a more recent study found an increased risk of agitation to be associated with greater NFT burden during early stages of the disease when NFTs are largely confined to the transentorhinal cortex and brainstem regions, including the LC.Reference Ehrenberg, Suemoto and Franca Resende 42 Second, despite the loss of LC neurons, positive correlations have been reported between NE levels within the PFC and aggression and between CSF levels of MHPG and behavioral symptom severity.Reference Vermeiren, Janssens and Aerts 43 , Reference Jacobs, Riphagen, Ramakers and Verhey 44 Studies of these relationships are inconsistent, and several failed to find significant associations between NE or MHPG levels and aggression.Reference Engelborghs, Vloeberghs and Le Bastard 45 –Reference Vermeiren, Van Dam, Aerts, Engelborghs and De Deyn 48 Third, agitation is associated with changes in NE receptor expression and function that may occur in response to the loss of LC neurons.Reference Sharp, Ballard, Chen and Francis 49 Finally, studies using yohimbine or clonidine to challenge the noradrenergic system in patients with AD indicate that agitation and aggression may be associated with greater responsiveness of the noradrenergic system. In one study, patients with AD showed greater increases in agitation compared to controls following yohimbine administration that correlated with CSF epinephrine levels.Reference Peskind, Elrod and Dobie 50 In a second study, aggression was elevated in patients with a blunted growth hormone (GH) response to clonidine, which is thought to reflect noradrenergic system overactivity, compared to patients with a preserved GH response.Reference Herrmann, Lanctot, Eryavec, Van Reekum and Khan 51
Noradrenergic system hyperactivity may impair prefrontal function and drive amygdala activity in part through the activation of α1-adrenoceptors. One study examining α1-adrenoceptor binding in the PFC found that both receptor density and receptor affinity were positively associated with aggression in patients with AD.Reference Sharp, Ballard, Chen and Francis 49 Evidence suggests that PFC neurons are highly sensitive to changing NE levels, which are mediated in part by the activation of different classes of adrenoceptors as the disease progresses. Low to moderate levels of NE engage high-affinity α2-adrenoceptors.Reference Arnsten, Raskind, Taylor and Connor 18 However, increasing NE levels lead to the desensitization of α2-adrenoceptors, particularly α2C-adrenoceptors, and engage lower-affinity α1-adrenoceptors.Reference Arnsten, Raskind, Taylor and Connor 18 , Reference Bucheler, Hadamek and Hein 52 Within the PFC, activation of α1-adrenoceptors is associated with impaired functioning.Reference Arnsten, Raskind, Taylor and Connor 18 In contrast, amygdala function is enhanced by activation of α1-adrenoceptors and stimulation of LC terminals, as demonstrated by increased fear- and anxiety-related behaviors in rodent studies, while antagonism of these receptors produces the opposite effect.Reference Ferry, Roozendaal and McGaugh 53 –Reference Gu, Piper and Branigan 55 Consistent with these findings, agents that act as α1-adrenoceptor antagonists have been reported to improve agitation and aggression in patients with AD compared to placebo.Reference Wang, Shofer and Rohde 56 –Reference Lee, Slomkowski and Hefting 58
The hypothesized role of noradrenergic system dysfunction in agitation in Alzheimer’s dementia is summarized in Figure 2. Following the loss of neurons in the LC, the noradrenergic system undergoes compensatory changes, including increased NE synthesis and sprouting of axonal projections by LC neurons with elevated expression of α1-adrenoceptors in the PFC.Reference Szot, White, Greenup, Leverenz, Peskind and Raskind 38 , Reference Szot, White, Greenup, Leverenz, Peskind and Raskind 39 Given the opposing effects of elevated NE levels on PFC versus amygdala function and the evidence linking elevated noradrenergic system activity to agitation behaviors, increased NE signaling may contribute to agitation in patients with AD by impairing the executive and supervisory function of the PFC and increasing amygdala activity.
Figure 2. Hypothetical model of noradrenergic system dysfunction underlying agitation in Alzheimer’s dementia. Neurodegeneration of LC neurons is accompanied by compensatory increases in noradrenergic system activity, including increased NE synthesis and sprouting of axonal projections by LC neurons and increased α1-adrenoceptor expression in the PFC. This increase in NE signaling could impair PFC function and increase amygdala activity through the activation of α1-adrenoceptors. Dashed orange circle indicates NE neuron loss. Bolded orange arrows indicate increased NE release. Abbreviations: AMG, amygdala; LC, locus coeruleus; NE, norepinephrine; PFC, prefrontal cortex.
Serotonin
AD is associated with marked serotonergic system deficits. The raphe nuclei of the brainstem, which are the major sources of 5-HT in the brain, show tau pathology during early stages of the disease and eventual loss of 5-HT neurons and their projections.Reference Braak, Thal, Ghebremedhin and Del Tredici 9 , Reference Lanctôt, Herrmann and Mazzotta 16 Corresponding to this loss of 5-HT neurons, decreased levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been reported in CSF and in multiple brain regions, including the PFC, amygdala, hippocampus, and temporal cortex.Reference Lanctôt, Herrmann and Mazzotta 16 , Reference Vermeiren, Janssens and Aerts 43 , Reference Garcia-Alloza, Gil-Bea and Diez-Ariza 59 Decreased levels of 5-HT receptors have been reported in multiple brain regions, including decreased levels of 5-HT1A receptors in the frontal cortex and hippocampus.Reference Lanctôt, Herrmann and Mazzotta 16 , Reference Lai, Tsang, Esiri, Francis, Wong and Chen 60
The serotonergic system plays a key role in regulating aggression and impulsivity, with decreased central 5-HT signaling being associated with increased aggression.Reference Puig and Gulledge 13 , Reference Duke, Begue, Bell and Eisenlohr-Moul 61 This may occur in part through the modulation of PFC and amygdala activity, as functional imaging studies of healthy adults show that lowered central 5-HT levels via acute tryptophan depletion can alter PFC activity, increase amygdala reactivity to emotional stimuli, and impact prefrontal-amygdala connectivity.Reference Evers, Sambeth, Ramaekers, Riedel and van der Veen 62 , Reference Passamonti, Crockett and Apergis-Schoute 63 Dysfunction of the serotonergic system is poised to contribute to agitation behaviors by further disrupting PFC and amygdala function.
Several studies have reported relationships between decreased 5-HT or 5-HIAA levels and agitation. One postmortem study associated overactivity in life, consisting of high ratings for walking more, walking aimlessly, and trailing or checking on carers, with decreased prefrontal 5-HT levels.Reference Garcia-Alloza, Gil-Bea and Diez-Ariza 59 , Reference Hope, Keene, Fairburn, McShane and Jacoby 64 Additional studies have reported negative correlations between agitation and 5-HIAA levels, particularly in the hippocampus but also in the PFC.Reference Vermeiren, Janssens and Aerts 43 , Reference Vermeiren, Van Dam, Aerts, Engelborghs and De Deyn 46 , Reference Vermeiren, Van Dam, Aerts, Engelborghs and De Deyn 48 Treatment with a selective serotonin reuptake inhibitor (SSRI) has been reported to reduce agitation in patients with AD.Reference Porsteinsson, Drye and Pollock 65 Decreased expression of 5-HT receptors, particularly in the temporal cortex, has been linked to agitation in patients with AD. One study reported a negative correlation between aggression and 5-HT1A receptor density in the temporal cortex,Reference Lai, Tsang and Francis 66 with the same research group reporting a similar trend in the hippocampus, although this result did not reach statistical significance.Reference Lai, Tsang, Esiri, Francis, Wong and Chen 60 Another study reported that overactivity, as defined above, was predictive of reduced 5-HT6 receptor levels in the temporal cortex.Reference Garcia-Alloza, Hirst, Chen, Lasheras, Francis and Ramirez 67 Agitation and aggression are associated with abnormal responses to serotonergic system challenge as indicated by greater increases in prolactin concentrations following fenfluramine—a serotonin-releasing agent, agonist of the serotonin 5-HT2 receptors, and σ1 receptor positive modulator—administration.Reference Mintzer, Brawman-Mintzer and Mirski 68 , Reference Lanctôt, Herrmann, Eryavec, van Reekum, Reed and Naranjo 69
The effects of 5-HT are mediated by 7 families of 5-HT receptors (5-HT1 to 5-HT7) expressed on both excitatory glutamatergic neurons and inhibitory interneurons.Reference Puig and Gulledge 13 5-HT1A receptors within the PFC and amygdala appear to be particularly important for modulating behaviors relevant to agitation, including aggression and impulsivity. In rodents, stimulation of 5-HT1A receptors in the PFC reduced aggression and impulsivity,Reference Puig and Gulledge 13 , Reference Centenaro, Vieira, Zimmermann, Miczek, Lucion and de Almeida 70 while stimulation of 5-HT1A receptors in the amygdala decreased amygdala activity as well as fear- and anxiety-related behaviors.Reference de Paula and Leite-Panissi 71 , Reference Stein, Davidowa and Albrecht 72 In healthy adults, PET imaging studies using a radioligand selective for the 5-HT1A receptor have shown correlations between aggressive or impulsive traits and 5-HT1A binding in the PFC and amygdala.Reference Parsey, Oquendo and Simpson 73 , Reference Witte, Floel and Stein 74 Finally, treatment with an agent acting as a 5-HT1A partial agonist has been reported to improve agitation symptoms in patients with AD.Reference Grossberg, Kohegyi and Mergel 57 , Reference Lee, Slomkowski and Hefting 58
The hypothesized role of serotonergic system dysfunction in agitation in Alzheimer’s dementia is summarized in Figure 3. The role of 5-HT signaling in regulating activity of key neural circuits combined with evidence of serotonergic system deficits in both agitation-related behaviors and AD suggests that 5-HT signaling deficits may contribute to agitation in patients with AD by contributing to the disruption of PFC and amygdala function. The key role of the 5-HT1A receptor in regulating aggression and impulsivity suggests that these behaviors and agitation in Alzheimer’s dementia may be mediated in part by altered activation of these receptors.
Figure 3. Hypothetical model of serotonergic system dysfunction underlying agitation in Alzheimer’s dementia. Loss of 5-HT inputs to the PFC combined with decreased 5-HT1A receptor expression and activation may contribute to PFC dysfunction and aggression, while loss of 5-HT inputs to the amygdala could result in increased amygdala reactivity via decreased 5-HT1A activation. Dashed green circle indicates 5-HT neuron loss. Dashed green arrows indicate decreased 5-HT release. Abbreviations: 5-HT, serotonin; AMG, amygdala; PFC, prefrontal cortex; RN, raphe nuclei.
Dopamine
Historically, the dopaminergic system has been viewed as being relatively spared in AD compared to the other monoamine neurotransmitter systems.Reference Lanctôt, Herrmann and Mazzotta 16 More recent studies suggest that, while AD is associated with relatively little loss of DA neurons, dopaminergic system dysfunction may contribute to cognitive deficits and NPS associated with AD. Recent imaging studies have reported that patients with AD exhibit disrupted connectivity of the mesocorticolimbic DA system, consisting of dopaminergic projections from the ventral tegmental area (VTA) to cortical and limbic areas.Reference Serra, D’Amelio and Di Domenico 14 , Reference Sala, Caminiti and Presotto 75
Relative sparing of dopaminergic projections in the context of serotonergic system disruption provides a foundation for the dysregulation of DA release, contributing to agitation and aggression.Reference Lanctôt, Herrmann and Mazzotta 16 Specifically, serotonergic projections to the substantia nigra (SN) and VTA regulate DA release from DA neurons.Reference Kelland, Freeman and Chiodo 76 , Reference Courtiol, Menezes and Teixeira 77 Given the evidence linking agitation in Alzheimer’s dementia to serotonergic system deficits, a decrease in 5-HT levels predicts an altered striatal DA release in response to specific stimuli.
The dopaminergic system is involved in a number of processes, including the regulation of voluntary movement and reward processing.Reference Lindenmayer 78 , Reference Delgado 79 Increased activation of the dopaminergic system has been linked to agitation and aggression, with rodent studies showing that aggression was associated with striatal DA release and activation of D2 receptors, while antagonism of striatal D2 receptors decreased aggression.Reference Beiderbeck, Reber, Havasi, Bredewold, Veenema and Neumann 80 –Reference Nikulina and Kapralova 82 Similarly, treatment with agents acting as D2 receptor partial agonists or antagonists has been reported to improve agitation and aggression in patients with dementia.Reference Grossberg, Kohegyi and Mergel 57 , Reference Lee, Slomkowski and Hefting 58 , Reference De Deyn, Katz, Brodaty, Lyons, Greenspan and Burns 83
The potential role of dysregulated DA release in agitation is supported by studies in patients with AD. Several studies reported that aggression was associated with relative preservation of the dopaminergic system as indicated by higher CSF and plasma concentrations of the DA metabolite homovanillic acid and greater cell count in the SN.Reference Lopez, Kaufer, Reiter, Carra, DeKosky and Palmer 84 –Reference Sweet, Pollock and Mulsant 86 Recently, agitation was linked with increased functional connectivity between the VTA and the hippocampus and cerebellum, supporting a potential role of altered DA release in agitation in Alzheimer’s dementia.Reference Serra, D’Amelio and Di Domenico 14
The hypothesized role of dopaminergic system dysfunction in agitation in Alzheimer’s dementia is summarized in Figure 4. The dopaminergic system is less severely impacted by AD pathology compared to the other monoamine neurotransmitter systems, and there is some evidence that agitation may be associated with relative preservation of DA signaling. Preservation of DA signaling combined with serotonergic system deficits could give rise to dysregulation of DA release in the striatum, contributing to increased agitation and aggression.
Figure 4. Hypothetical model of dopaminergic system dysfunction underlying agitation in Alzheimer’s dementia. Preserved dopaminergic projections combined with a loss of regulation of DA release by serotonergic neurons could result in activation of striatal D2 receptors, which are implicated in agitated and aggressive behaviors. Dashed green and solid purple circles indicate 5-HT neuron loss and DA neuron preservation, respectively. Dashed green and bolded purple arrows indicate decreased 5-HT release and increased DA release, respectively. Abbreviations: 5-HT, serotonin; DA, dopamine; RN, raphe nuclei; SN, substantia nigra; STR, striatum; VTA, ventral tegmental area.
Summary of monoamine neurotransmitter system dysfunction in agitation in Alzheimer’s dementia
The potential roles of the monoamine neurotransmitter systems in agitation in Alzheimer’s dementia are summarized in Figure 5. This evidence-based model suggests that agitation arises from an imbalance between executive control mediated by prefrontal brain regions and emotional drive provided by subcortical brain regions, including the amygdala.Reference Rosenberg, Nowrangi and Lyketsos 10 , Reference Carrarini, Russo and Dono 11 AD is associated with marked alterations in the monoamine neurotransmitter systems, providing the basis for this imbalance.Reference Serra, D’Amelio and Di Domenico 14 –Reference Lanctôt, Herrmann and Mazzotta 16 Noradrenergic system hyperactivity combined with serotonergic system deficits may result in PFC dysfunction and elevated amygdala reactivity, while dysregulated DA release in the striatum may contribute to agitated and aggressive behaviors.
Figure 5. Hypothetical model of monoamine neurotransmitter system dysfunction underlying agitation in Alzheimer’s dementia. Increased NE signaling combined with 5-HT signaling deficits may contribute to PFC dysfunction and increased amygdala reactivity through the increased activity of α1-adrenoceptors and decreased activity of 5-HT1A receptors. Dysregulated DA signaling may contribute to agitation and aggression via activation of striatal D2 receptors. Collectively, these effects contribute to an imbalance between executive control and emotional drive. Dashed orange and green circles indicate NE and 5-HT neuron loss, respectively. Solid purple circle indicates DA neuron preservation. Bolded orange and purple arrows indicate increased NE and DA release, respectively. Dashed green arrows indicate decreased 5-HT release. Abbreviations: 5-HT, serotonin; AMG, amygdala; DA, dopamine; LC, locus coeruleus; NE, norepinephrine; PFC, prefrontal cortex; RN, raphe nuclei; SN, substantia nigra; STR, striatum; VTA, ventral tegmental area.
Other Neurotransmitter Systems
While evidence suggests that disruption of the monoamine neurotransmitter systems may be a key aspect of agitation in Alzheimer’s dementia pathophysiology, disruption of other neurotransmitter systems, such as glutamate and γ-aminobutyric acid (GABA), may also contribute to agitation symptoms.
Glutamate is the primary excitatory neurotransmitter in the brain, with glutamatergic projections from the PFC providing top-down control over subcortical regions, including the amygdala.Reference Ray and Zald 17 AD is associated with dysfunctional glutamate transmission, which may contribute to agitation and aggression by disrupting frontal cortex function (Figure 6).Reference Francis 87 Patients with AD show reduced glutamate reuptake in multiple brain regions, including the frontal cortex, possibly reflecting interference by Aβ plaques with the function of glutamate transporters.Reference Francis 87 , Reference Esposito, Belli, Toniolo, Sancesario, Bianconi and Martorana 88 Decreased reuptake could result in elevated glutamate levels as indicated by studies reporting elevated CSF levels of glutamate and its precursor glutamine in patients with AD.Reference Madeira, Vargas-Lopes and Brandao 89 Elevated glutamate levels may disrupt frontal cortex function, with elevated levels impairing normal cognitive processes and extreme elevations driving excitotoxicity through extrasynaptic glutamate N-methyl-D-aspartate (NMDA) receptors.Reference Francis 87 , Reference Esposito, Belli, Toniolo, Sancesario, Bianconi and Martorana 88 Agents acting as NMDA receptor antagonists improve agitation in patients with AD.Reference O’Gorman, Jones, Cummings and Tabuteau 90
Figure 6. Hypothetical model of glutamatergic system dysfunction underlying agitation in Alzheimer’s dementia. Decreased glutamate reuptake may contribute to increased NMDAR activation, resulting in PFC neuron dysfunction and excitotoxicity. Decreased top-down regulation from the PFC may result in increased amygdala reactivity. Dashed blue arrow indicates decreased PFC regulation of the amygdala. Abbreviations: AMG, amygdala; NMDAR, N-methyl-D-aspartate receptor; PFC, prefrontal cortex.
GABA is the primary inhibitory neurotransmitter in the brain.Reference Xu, Zhao, Han and Zhang 91 During normal brain activity, activation of excitatory glutamatergic neurons and inhibitory GABAergic interneurons maintains a balance of activity within neural circuits.Reference Xu, Zhao, Han and Zhang 91 , Reference Li, Sun, Chen, Xu, Bu and Zheng 92 While GABAergic neurons and receptors have been viewed as being more resistant to AD pathology than other systems, recent research indicates that the GABAergic system undergoes substantial changes in AD.Reference Li, Sun, Chen, Xu, Bu and Zheng 92 Tau pathology and neurodegeneration of GABAergic interneurons have been observed in multiple brain regions, including the hippocampus and cortex, along with decreases in brain and CSF levels of GABA.Reference Xu, Zhao, Han and Zhang 91 , Reference Li, Sun, Chen, Xu, Bu and Zheng 92 Disruption of GABAergic neuron function may lead to an imbalance between excitation and inhibition within neural circuits, potentially contributing to cognitive impairments and behavioral disturbances in AD.Reference Xu, Zhao, Han and Zhang 91 , Reference Li, Sun, Chen, Xu, Bu and Zheng 92
Insights From Emerging Pharmacological Treatments
The increasing prevalence of AD and the burden of agitation in Alzheimer’s dementia for patients and caregivers alike underscore the need for new therapies that can address NPS, including agitation in patients with AD. One agent, brexpiprazole, has been approved by the US Food and Drug Administration (May 2023) for the treatment of agitation associated with dementia due to Alzheimer’s disease, and 6 agents being developed for treatment of agitation symptoms in patients with AD are in phase 3 clinical trials (as per the federal database ClinicalTrials.gov on September 25, 2023): dexmedetomidine (α2-adrenoceptor agonist), citalopram (SSRI), masupirdine (5-HT6 antagonist), AVP-786 (dextromethorphan plus quinidine), AXS-05 (dextromethorphan plus bupropion), and nabilone (cannabinoid partial agonist). Consistent with the proposed role of monoamine neurotransmitter system dysfunction in agitation in Alzheimer’s dementia, 2 of the 6 agents currently in phase 3 clinical trials, along with brexpiprazole, act on the noradrenergic, serotonergic, or dopaminergic systems.
Brexpiprazole has a high affinity for noradrenergic α-adrenoceptors, in addition to its high affinity for serotonergic and dopaminergic receptors. Brexpiprazole acts as an antagonist at α1B-adrenoceptors while also serving as a partial agonist at 5-HT1A serotonergic and D2 dopaminergic receptors.Reference Grossberg, Kohegyi and Mergel 57 , Reference Maeda, Sugino and Akazawa 93 Additionally, brexpiprazole acts as an antagonist at α2C-adrenoceptors and 5-HT2A serotonergic receptors.Reference Maeda, Sugino and Akazawa 93 Hypothetically, α1B-adrenoceptor antagonism and 5-HT1A partial agonism may support PFC function and reduce amygdala function by blocking the deleterious effects of elevated NE and restoring 5-HT signaling, while D2 receptor partial agonism may regulate striatal DA activity.
Dexmedetomidine is an α2-adrenoceptor agonist currently used in intensive care units for its sedative properties and has been proposed as an acute treatment for agitation.Reference Weerink, Struys, Hannivoort, Barends, Absalom and Colin 94 Consistent with the hypothesized role of noradrenergic hyperactivity in agitation in Alzheimer’s dementia, the effects of dexmedetomidine are thought to be mediated by the activation of presynaptic α2-autoreceptors, which inhibit NE release.Reference Gertler, Brown, Mitchell and Silvius 95
Citalopram is an SSRI whose clinical benefits are primarily associated with its S-enantiomer (escitalopram).Reference Porsteinsson, Drye and Pollock 65 , Reference Ho, Pollock and Mulsant 96 The efficacy of SSRIs is believed to be driven in part by the desensitization of somatodendritic 5-HT1A autoreceptors ultimately resulting in increased 5-HT release in target regions, which is consistent with the hypothesized role of serotonergic system deficits in agitation in Alzheimer’s dementia.Reference Grinchii and Dremencov 97
Although not currently in phase 3 clinical trials as per ClinicalTrials.gov, prazosin is a centrally acting α1-adrenoceptor antagonist previously shown to improve behavioral symptoms in AD patients with agitation and aggression.Reference Wang, Shofer and Rohde 56 Hypothetically, antagonism of postsynaptic α1-adrenoceptors may address agitation symptoms by preventing the effects of noradrenergic hyperactivity.
Four of the 6 agents in phase 3 clinical trials act on targets beyond the monoamine neurotransmitter systems. Masupirdine is a serotonin 5-HT6 receptor antagonist whose efficacy may arise from modulation of neurotransmitters implicated in agitation, including glutamate, GABA, and NE, as well as acetylcholine.Reference Cummings 98 , Reference Nirogi, Jayarajan and Benade 99
AVP-786 is the deuterated form of AVP-923, a combination of the NMDA receptor antagonist and σ1 receptor agonist dextromethorphan and the cytochrome P450 2D6 (CYP2D6) inhibitor quinidine.Reference Khoury, Marx, Mirgati, Velury, Chakkamparambil and Grossberg 100 AXS-05 is a combination of dextromethorphan and the NE and DA reuptake inhibitor and CYP2D6 inhibitor bupropion.Reference O’Gorman, Jones, Cummings and Tabuteau 90 NMDA receptor antagonism may reduce agitation by protecting against the effects of elevated glutamate transmission, such as disrupted frontal cortex function.
Nabilone is a synthetic cannabinoid that acts as a partial agonist at cannabinoid CB1 and CB2 receptors.Reference Herrmann, Ruthirakuhan and Gallagher 101 Nabilone may indirectly influence the neurotransmitter systems implicated in agitation, as the endocannabinoid system modulates the activity of other neurotransmitter systems, including the monoamine, glutamatergic, and GABAergic systems.Reference Brunt and Bossong102 Cannabinoid receptors are expressed in brain regions associated with monoaminergic signaling, including the amygdala, cerebral cortex, basal ganglia, and striatum, and evidence suggests that cannabinoid receptor expression is correlated with tauopathy and subsequent neurodegeneration.Reference Brunt and Bossong 102 , Reference Galan-Ganga, Rodriguez-Cueto and Merchan-Rubira 103
Limitations
One limitation of this review is the potential impact of other NPS, as patients with dementia frequently experience multiple NPS.Reference Goodwin, Moeller, Nguyen, Cummings and John 104 While this review focused on studies of patients with agitation in Alzheimer’s dementia, it is possible that the study results were influenced by the presence of additional NPS.
A second limitation is that the proposed pathophysiology of agitation in Alzheimer’s dementia discussed in this review does not distinguish between domains of agitation, which include excessive motor activity, verbal aggression, and physical aggression, as it has been suggested that different aspects of agitation may arise from different structural and functional deficits.Reference Cummings, Mintzer and Brodaty 4 , Reference Rosenberg, Nowrangi and Lyketsos 10 , Reference Lindenmayer 78 While there has been relatively little study of the pathophysiology associated with different domains of agitation, several studies discussed in this review provide potential insights. PFC dysfunction was associated with multiple forms of agitation, including aggression and aberrant motor behavior, as well as physical and verbal agitation, suggesting that loss of executive control may contribute to multiple agitation domains.Reference Tekin, Mega and Masterman 20 , Reference Hu, Meiberth, Newport and Jessen 23 , Reference Hirono, Mega, Dinov, Mishkin and Cummings 27 , Reference Banno, Nakaaki and Sato 28 , Reference Valotassiou, Sifakis and Tzavara 30 Additionally, several studies reported that alterations in the noradrenergic system were associated with aggressive behavior but not overactivity or physically nonaggressive behavior, suggesting that noradrenergic system dysfunction may be particularly important in the development of verbal or physical aggression.Reference Matthews, Chen, Esiri, Keene, Minger and Francis 41 –Reference Vermeiren, Janssens and Aerts 43 , Reference Sharp, Ballard, Chen and Francis 49 Further study of the pathophysiology underlying different agitation domains would improve understanding of the neurobiological basis of NPS in AD.
Conclusion
This review synthesized research observations to provide a hypothetical model for the pathophysiology of agitation in Alzheimer’s dementia with a focus on the monoamine neurotransmitter systems. Agitation may arise from disrupted top-down executive control and elevated bottom-up emotional drive mediated by prefrontal and subcortical brain regions, respectively. The monoamine neurotransmitter systems are key modulators of these brain regions and show marked alterations in AD. Noradrenergic hyperactivity along with serotonergic deficits and dysregulated dopamine release may contribute to agitation symptoms by disrupting the balance between executive control and emotional drive. These neurotransmitter abnormalities may point to development of specific types of agents useful in the control of agitation.
Acknowledgments
Editorial assistance for the preparation of this manuscript was provided by Donnie Pickel, PhD, and Lauren Hummel, BA, each of Metis Medical Media (Carlsbad, CA, USA), which was supported by Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck. The authors are entirely responsible for the scientific content of this manuscript.
Author contribution
Conceptualization: S.M.S., M.P., J.L.C., K.J.S., M.B.; Data curation: S.M.S., M.P., M.B., S.T.G.; Funding acquisition: S.M.S., M.P., M.B.; Investigation: S.M.S., M.P., M.B., S.T.G.; Methodology: S.M.S., M.P., J.L.C., K.J.S., M.B., S.T.G.; Project administration: S.M.S., M.P., J.L.C., M.B.; Resources: S.M.S., M.P., K.J.S., M.B.; Software: S.M.S., M.P., M.B.; Supervision: S.M.S., M.P., J.L.C., M.B.; Validation: S.M.S., M.P., M.B.; Visualization: S.M.S., M.P., J.L.C., K.J.S., M.B., S.T.G.; Writing – original draft: S.M.S., M.P., K.J.S., M.B., S.T.G.; Writing – review & editing: S.M.S., M.P., J.L.C., K.J.S., M.B., S.T.G.; Formal analysis: S.M.S., M.P., J.L.C., M.B.
Financial support
This work was funded by Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck.
Competing interests
Jeffrey L. Cummings, MD, has provided consultation to Acadia, Actinogen, Acumen, Alpha Cognition, ALZpath, APRINOIA, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol Myers Squibb, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, LSP/EQT Life Sciences, Lundbeck, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, ONO, OptoCeutics, Otsuka, Oxford Brain Diagnostics, Prothena, reMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. Dr. Cummings is supported by NIGMS grant P20GM109025, NINDS grant U01NS093334, NIA grant R01AG053798, NIA grant P30AG072959, NIA grant R35AG71476, NIA R25 AG083721–01, Alzheimer’s Disease Drug Discovery Foundation (ADDF), Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment.
Malaak Brubaker, PhD, is an employee of Otsuka Pharmaceutical Development & Commercialization, Inc.
Katherine J. Selzler, PhD, was an employee of Lundbeck at the time this work was completed. Dr. Selzler is also a former employee and minor shareholder of Eli Lilly and Company.
Sarah T. Gonzalez, PhD, has nothing to disclose.
Mehul Patel, PharmD, is an employee of Otsuka Pharmaceutical Development & Commercialization, Inc.
Stephen M. Stahl, MD, PhD, DSc (Hon), is a Clinical Professor of Psychiatry and Neuroscience at the University of California, Riverside; an Adjunct Professor of Psychiatry at the University of California, San Diego; Honorary Visiting Senior Fellow at the University of Cambridge; Director of Psychopharmacology for the California Department of State Hospitals; and Editor in Chief for CNS Spectrums. From January 2023 to December 2023, Dr. Stahl served as a consultant to AbbVie/Allergan, Acadia, Alkermes, Altus, Axsome, Cerevel, Clearview, Clexio, Compass Pathways, Delix, Done, Enveric Biosciences, Fabre-Kramer, Gedeon Richter, Genetika, Intra-Cellular Therapies, Janssen, Karuna Therapeutics, Leal Therapeutics, Libbs, Lipidio, LivaNova, Longboard, Lundbeck, Merck, MS Pharma, NeuraWell, Neurocrine Biosciences, Otsuka, Recordati, Relmada Therapeutics, Sage Therapeutics, Saniona, Sunovion, Supernus, Teva, Tonix, Tris Pharma, and Vanda. He holds options in Delix, Genomind, Lipidio, and NeuraWell. He has served on speakers bureaus for AbbVie/Allergan, Intra-Cellular Therapies, Karuna Therapeutics, and Lundbeck, and he has received research and/or grant support from Acadia, AbbVie/Allergan, Avanir, Boehringer Ingelheim, Braeburn Pharmaceuticals, Daiichi Sankyo, Eisai Brazil, Eli Lilly, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, Neurocrine, Otsuka, Pear Therapeutics, Sage, Shire, Sunovion, Supernus, and Torrent.
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