Serotonergic system, cognition, and BPSD in Alzheimer’s disease

Neuroscience Letters 704 (2019) 36–44

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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet

Review article

Serotonergic system, cognition, and BPSD in Alzheimer’s disease a

a

b

c

T a

Saikat Chakraborty , Jack C. Lennon , Sridhar A. Malkaram , Yan Zeng , Daniel W. Fisher , ⁎ Hongxin Donga, a b c

Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL, 60611, USA Department of Biology, West Virginia State University Institute, WV-25112, USA Brain and Cognition Research Institute, Wuhan University of Science and Technology, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Behavioral and psychological symptoms of dementia (BPSD) Alzheimer's disease 5-hydroxytryptamine (5-HT) 5-HT receptors (5-HTRs)

Behavioral and Psychological Symptoms of Dementia (BPSD), present in almost 90% of patients with Alzheimer's Disease (AD), cause extensive impairment leading to reduced independence and inability to complete activities of daily living. Though BPSD includes a wide range of symptoms, such as agitation, aggression, disinhibition, anxiety, depression, apathy, delusions, and hallucinations. Certain BPSD in AD co-present and can be clustered into distinct domains based on their frequency of co-occurrence. As these BPSD are so pervasive in any stages of AD, the disease may be better characterized as a disorder of heterogeneous degenerative symptoms across a number of symptom domains, with the most prominent domain comprising memory and cognitive deficits. Importantly, there are no FDA-approved drugs to treat these BPSD, and new approaches must be considered to develop effective treatments for AD patients. The biogenic monoamine 5-hydroxytryptamine (5-HT), or serotonin, works as both a neurotransmitter and neuromodulator, which has been tied to cognitive decline and multiple BPSD domains. This review summarizes the evidence for specific serotonergic system alterations across some of the well-studied cognitive, behavioral, and psychiatric domains. Though differences in overall serotonergic transmission occur in AD, circuit-specific alterations in individual 5-HT receptors (5-HTRs) are likely linked to the heterogeneous presentation of BPSD in AD.

1. Introduction Alzheimer’s Disease (AD) is a neurodegenerative disorder that leads to severe memory impairments and cognitive decline, but over 90% of AD patients also develop significant Behavioral and Psychological Symptoms of Dementia (BPSD), including agitation, aggression, irritation, disinhibition, anxiety, depression, apathy, delusions, and hallucinations [1,2]. For both patients and caregivers, these BPSD in AD can be as detrimental as the cognitive deficits, resulting in worse prognoses, greater impairments in activities of daily living [3], increased dependence on outside care [4], and increased health care costs [1]. Highlighting the clinical importance of these symptoms, BPSD are the leading reason for loss of independence and institutionalization for AD [5,6]. The high burden of these BPSD suggest that AD may be better characterized as a disorder of heterogeneous degenerative symptoms across a number of behavioral domains, with the most prominent being memory deficits. In line with this perspective, many groups have noticed that certain BPSD in AD often co-present and can be clustered into

distinct domains based on their frequency of co-occurrence [7]. In a recent systematic review covering 62 studies of unbiased approaches to cluster these symptoms, the following domains were identified: Affective (anxiety and depression), Disinhibition/hyperactivity (aggression, impulsivity, motor hyperactivity), Apathy, Psychosis (hallucinations, delusions, paranoia), and Elation [7,6]. Unfortunately, even with some classification of these domains clinically, there remains no FDA-approved options to treat any of the BPSD, and off-label pharmacological approaches perform poorly for AD patients [8,9]. The high degree of co-presentation of symptoms across domains suggests a possible common perturbation of signaling pathways or neural circuitry specific to each domain. Interestingly, the biogenic monoamine 5-hydroxytryptamine (5-HT), or serotonin, has been tied to cognitive decline and multiple other BPSD domains [10–12]. 5-HT acts as a tissue hormone, neurotransmitter, and neuromodulator acting in both central and peripheral systems [13,14] (Table 1). Serotonin is one of the most extensively studied neurotransmitters in the Central Nervous System (CNS) regulating multiple physiological functions [15]. The projections from the raphe nuclei, where 5-HT is produced, are

⁎ Corresponding author at: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Ward 7103, Chicago, IL, 60611, USA. E-mail address: [email protected] (H. Dong).

https://doi.org/10.1016/j.neulet.2019.03.050 Received 15 November 2018; Received in revised form 26 March 2019; Accepted 27 March 2019 Available online 01 April 2019 0304-3940/ © 2019 Elsevier B.V. All rights reserved.

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Table 1 Classification, distribution, and functions of 5-HTRs. Receptor family

Receptor subtypes

Distribution of receptor families CNS

5-HTR1 5-HTR2 5-HTR3 5-HTR4 5-HTR5 5-HTR6 5-HTR7

1A/1B/1D/1E/1F 2A/2B/2C 3A/3B None known 5A/5B None known None known

x x x x x x x

PNS

x x x

Blood vessels

Platelets

Smoothmuscles

x x

x

x

Cellular Response

Adenylate cyclase Phospholipase C Ligand-gated ion channel Adenylate cyclase Adenylate cyclase Adenylate cyclase Adenylate cyclase

↓ ↑ ↑ ↑ ↓ ↑ ↑

GI

x

x

Effector Mechanism

x

Abbreviations: CNSCentral Nervous System; PNSPeripheral Nervous System; GIGastrointestinal track. A modification of Translational Neuroscience 2016;7:35-49.

Serotonergic systems putatively affect cognition through their activity in two main brain areas: the hippocampus and prefrontal cortex. 5-HT in the hippocampus is involved in spatial navigation, decision making, and social relationships [27,28] while, in the prefrontal cortex, 5-HT plays a major role in working memory, attention, decision making, and reversal learning in both human and animals [29,30]. Aging is the most important risk factor for AD, and declines in certain 5-HTRs in cognition-related brain areas are well-documented with advancing age. During aging, the activity and density of 5-HTR1A, which is known to affect declarative and non-declarative memory decline by approximately 10% every ten years [31]. Further age-dependent decreases in 5-HTR2A are also observed in the hippocampus and frontal cortex of healthy individuals at a similar rate [32], correlating clinically with cognitive decline [33]. Finally, 5-HTR4 agonist reverses scopolamine-induced cognitive defects pre-clinically [34], likely through regulation of synaptic plasticity [35], though the overall expression of 5-HTR4 is unlikely to change with aging [36]. Overall, brain area- and 5-HTR-specific alterations that occur with aging may lower cognitive reserve in pre-AD patients and may influence the rate of cognitive decline with AD pathogenesis. Altered expression of 5-HTRs also directly influences the pathogenic molecules underlying AD as well as contributing to AD-related cognitive decline. Broadly, there is extensive serotonergic denervation in AD [37], with reductions in 5-HT as well as its metabolites in post-mortem AD brains [38,37]. Similar to aging, reductions in 5-HTRs are seen in a subunit- and brain region-specific manner with AD pathogenesis. 5HTR1A declines progressively with worsening cognitive impairment in the hippocampus and dorsal raphe of patients with mild cognitive

widespread across the CNS, including ascending to the cerebral cortex, thalamus, hypothalamus, and basal ganglia, and descending to the brainstem and spinal cord [16–18]. As might be expected by 5-HT’s many projections, serotonergic circuitry has been implicated in a number of basal and higher brain functions that are perturbed in BPSD [15,19–22]. Despite the pan-CNS nature of 5-HT transmission, circuit and functional specificity is achieved via diverse expression of 14 5-HT receptor (5-HTR) subunits, each with varying downstream signaling functions and brain area-specific expression in humans and animals (Table 2). Thus, it is highly possible that the co-clustering of BPSD into domains depends on the circuit- and 5-HTR subunit-specific alterations that occur with AD pathogenesis and further interact with a person’s innate neural architecture. In this review, we summarize the evidence for specific serotonergic system alterations across some of the welldefined behavioral and psychological symptoms in AD, including cognitive and memory, affective, hyperactivity/irritation/disinhibition/ aggression (HIDA), apathy and psychosis domains. Other behavioral changes such as sleep disruption and elation in AD, are excluded. The literature we collected for this review started from 1990 to date, based on the Pubmed and Google search.

2. Cognition and memory domain Serotonergic systems has been highly implicated in influencing cognition and memory in health and across multiple pathological disease states [23,24], and serotonergic systems perturbations have been associated with memory decline in AD specifically [25,26]. Table 2 5HTR distribution in animal and human brains specific to symptom group. 5-HTR family

5-HTR1 5-HTR2

Symptom group(s)

Cognition BPSD Cognition BPSD

5-HTR3 5-HTR4 5-HTR5

5-HTR6 5-HTR7

Cognition BPSD Cognition BPSD Cognition BPSD Cognition BPSD Cognition BPSD

Distribution and Changes Animal

Human

Hippocampus [139], prefrontal cortex [18] Frontal, temporal [104,26], amygdala [80] Hippocampus [139], prefrontal cortex [18,80], amygdala [80] Frontal [105], temporal [80], cingulate, hippocampus, amygdala [80] Prefrontal cortex [18], limbic system [139] Amygdala, hippocampus [57] Hippocampus [43,140], prefrontal cortex [12] Frontal [44], amygdala [80], hippocampus [43] Hippocampus [139], prefrontal cortex [12], amygdala [12] Unknown Hippocampus [139] Hippocampus [49], dorsal raphe nucleus [49] Hippocampus [59], thalamus [12], raphe nuclei [141], cerebral cortex [141] Hippocampus [80]

Hippocampus [139], rostral raphe nuclei [12,80], temporal cortex [40] Unknown Hippocampus [139], prefrontal cortex [48]

37

Prefrontal [79,102], bed nucleus of stria termalis [78], amygdala [78], hippocampus [78], nucleus accumbens [102,105] Hippocampus [57,139] Hippocampus [86], amygdala [86] Hippocampus [42], nucleus accumbens [87] Hippocampus [42], cerebrum [99] Prefrontal cortex [12], amygdala [12], hypothalamus [12] Hippocampus [12], prefrontal cortex [12] Prefrontal cortex [48], temporal cortex [40] Neocortex [85] Hippocampus [12,60], raphe nuclei [141], cerebral cortex [141] Prefrontal cortex [12], hippocampus [12]

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Fig. 1. Serotonin Receptor Distribution in Hippocampus and Prefrontal Cortex Associated with Cognition [142–150].

[56], again suggesting a protective role for 5-HTR4 in AD. The role of 5HTR6 contrasts with 5-HTR4, as blocking 5-HTR6 in an Aβ-42 -infused mouse model leads to reduced Aβ formation via the inhibition of γsecretase and the inactivation of astrocytes and microglia [49], consistent with improved cognition with 5-HTR6 antagonism. Lastly, 5HTR7 receptor activation improves synaptic dysfunction in a rat model of AD via reduction of apoptosis in the hippocampus, which could potentially prevent the progression of AD [59]. Additionally, several studies have demonstrated improvement in cognitive function in patients with AD treated with selective serotonin reuptake inhibitors (SSRIs) [60,61]. One of the main themes that emerges from this complex interplay between 5-HTR subunits and AD pathogenesis is that no single mechanism of global 5-HT transmission is sufficient to capture the effects of these diverse serotonergic circuits on AD-related cognitive decline. Instead, the expression and regulation of each 5-HTR subunit requires consideration in determining how modulation of these circuits will affect the cognitive function in AD patients. Further, as many of these 5HTRs are able to affect cognition independent of AD status, future experiments with careful experimental design will be necessary to determine whether the function of individual 5-HTRs affect AD-related cognitive decline, cognition independent of AD, or both entities.

impairment (MCI) and AD [39]. 5-HTR1B is similarly reduced in the frontal and temporal cortices and is also associated with the level of cognitive dysfunction [40]. For 5-HTR2A, the severity of cognitive impairment in AD patients correlate with the receptor’s decreased expression in the temporal lobe [41,26]. While 5-HTR4 expression is not reduced with aging, there is significant reduction of the receptor in the post-mortem hippocampi and cortices of AD patients [42,43], dovetailing with preclinical evidence demonstrating improved cognition in an AD mouse model with chronic, partial agonism of 5-HTR4 [44]. Finally, 5-HTR7 agonism is suggested to improve cognitive function in rodent AD models [45], and clinical trials investigating 5-HTR7 agonists as a therapeutic approach for AD are ongoing [46]. In contrast to 5-HTR1, 5-HTR2, 5-HTR4, and 5-HTR7, reduction in or inhibition of other 5-HTRs improves cognition in AD. For instance, inhibition of 5-HTR3 alleviates spatial memory deficits in an AD rat model [47]. Interestingly, while there is also a reduction in 5-HTR6 positive neurons in AD patients [48], multiple pre-clinical and clinical studies have shown improvement in cognition with 5-HTR6 antagonists [49–51], suggesting a more complex role for this receptor in AD-related cognitive decline (Fig. 1). Though the mechanisms underlying 5-HTR-mediated effects on cognition in AD are not completely elucidated, preclinical evidence exists for how certain 5-HTRs affect the main pathological molecules implicated in AD pathogenesis, namely Aβ and hyperphosphorylated tau. For instance, an AD mouse model overexpressing Aβ (APP/PS1 mice) demonstrated that pathological accumulation of Aβ dependented with decrease of 5-HTR2A expression [52]. NMDA receptors may also interact with the serotonin system, most notably with postsynaptic 5HT2A receptors [8]. Since presynaptic glutamate release is affected in APP/PS1 mice [53], amyloid-induced dysfunction in glutamatergic transmission might mediate the disrupted serotonin system. In addition, antagonism of 5-HTR2C prevents tau hyperphosphorylation and reverses defects in hippocampal long-term potentiation and spatial memory [54]. Conversely, however, stimulation of 5HTR2C with dexnorfenfluramine enhances in vitro and in vivo secretion of non-pathogenic APP metabolites and reduces Aβ production [55,56]. 5-HTR3 antagonism leads to reduced Aβ-induced neurotoxicity in cultured rat cortical neurons [57]. Chronic agonism of 5-HTR4 in the 5xFAD mouse model slows down the formation of Aβ plaques and promotes α-secretase cleavage of APP, leading to non-pathological APP metabolites [44]. In the hAPP/PS1 mouse model, 5-HTR4 agonism decreases the amount of both soluble and insoluble Aβ in the brain

3. Affective domain Serotonergic system dysfunctions are important factors for affective disorders where anxiety and depression are major components [62,63]. Numerous clinical and preclinical studies have found roles of serotonin transporter (5-HTT) [64–67], tryptophan hydroxylase 2 (TPH2) [68,69], 5-HTR1A [70–76] and 5-HTR2A [77–79] in affective symptoms, highlighting the complexity of serotonergic influence on affective symptoms outside of patients with dementia. Yohn and colleagues provide a review suggesting that numerous 5-HTRs are implicated in depressive symptoms in both human and animal models [80]. Surprisingly, human studies have been mixed in terms of the effect of polymorphisms among serotonergic system genes. For instance, the 5-HTR2A T102C polymorphism has been associated with increasing depression symptoms in some studies while not showing any associations in others [81–83]. A similar mix of positive and negative studies are also present for the 5-HTR2C G68C (C23S) polymorphism and ADassociated affective symptoms risk [82]. For 5-HTR6 C267T and the 5HTTLPR polymorphisms, no associations were found for depression 38

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5-HTR1A [98,103]. In AD, aggression has been associated with reduction in 5-HTR1A in the medial temporal cortex [104,26]. Interestingly, in an association study conducted on a Finnish population, the T102C 5-HTR2B polymorphism was associated with aggressive behavior [105]. This study, however, utilized a sequencing method from a large cohort of violent offenders that shared many characterological correlates of aggression and impulsivity. The GWAS was done in humans and identified an association between HTR2B*rs1744037 and cannabis-related aggression. This was validated in an animal study using Htr2b-/KO mice that received THC in the resident intruder paradigm. These findings strongly suggests a moderating role of 5-HTR2B on cannabisinduced aggressive behavior [106]. Additionally, decreased serotonin levels have been associated with behavioral disinhibition in mice [107]. In AD, frontal lobe symptoms such as “loss of insight and judgment” have been associated with polymorphisms in 5-HTT and TPH2 [97]. Therapeutically, one study noted that the 5-HTR1A partial agonist tandospirone reduced agitation, aggression, and irritation in AD patients [94]. However, meta-analyses have found only weak evidence to support SSRI use for the treatment of agitation in AD, especially when compared to antipsychotics [92].

symptoms in AD [82,84], though one study noted higher anxiety symptoms with the 5-HTTLPR LL genotype [85]. There is also evidence to suggest that anxiety disorders such as obsessive-compulsive disorder may be linked to HTR3 variants [86] while overexpression, increased density, and mRNA content of nucleus accumbens (NAc) 5-HTR4 triggered anorexic behaviors [87]. In a non-genetic analysis of receptor density and occupancy, 5HTR1A was found to be less abundant in patients with AD and “apparent” sadness, though no associations with 5-HTR2A or 5-HTT and depression symptoms were detected [41,26]. However, no association between 5-HTT [88] and serotonergic neuronal density in the dorsal raphe [89] and depression were found for AD patients. One interesting preclinical study noted an increase in depression-like symptoms with intracerebroventricular injection of Aß oligomers which was dependent on decreased 5-HT concentrations leading to increased microglial activation and TNF1 signaling, though the individual 5-HTRs mediating this effect were not investigated [90]. In addition, studies examining the effects of SSRIs on affective symptoms have been mixed, highlighted by a systematic review that identified seven out of eleven clinical trials showing improvement in non-cognitive symptoms, including affective domain symptoms among others [91]. Similarly, meta-analyses of randomized trials have found only tenuous support for the use of SSRIs for treating dementia-associated depression [92,93]. Supporting the importance of subunit specificity, the 5-HTR1A partial agonist tandospirone improved anxiety and depression symptoms in 13 patients with dementia over a fourweek course of treatment [94]. These mixed results indicate the heterogeneity of serotonergic influences on the affective domain in AD and suggest that future studies examining factors that influence brain region-specific and 5-HTR subunit expression and functioning are necessary to parse out the role of this complex system on these symptoms.

5. Apathy domain Apathy, a group of negative symptoms that displays absence or suppression of passion, emotion, or excitement, is highly prevalent (70–90%) in AD [108]. Apathy is often underdiagnosed and undertreated [109] but presents as a very significant problem in patients with AD, as patients stop completing activities of daily living [110]. Apathy can occur separately or in combination with depression and anxiety and is one of the most frequently encountered neuropsychiatric symptoms where serotonergic degeneration play an important role [111]. Along with dopamine, serotonin is the major neurotransmitter linked to motivation [112]. Though loss of interest in daily activities is also a key symptom of depression, the impact of SSRIs on motivational deficits related to apathy instead of anhedonia remain controversial [113–116] In BPSD, apathy rarely leads to hospital admissions [117], but it is associated with poor prognosis and increased mortality [118,119]. Treatment of apathy lacks standard guidelines. Aripiprazole, a novel antipsychotic with partial agonistic properties at serotonin 5-HTR1A and dopamine receptor 2 (D2) receptors had significant success in relieving symptoms of apathy [120]. 5HTR2A polymorphism T102C is reported to be associated with apathy [121]. However, despite these few studies, little is known about the correlation between serotonergic signaling and apathy in AD.

4. Hyperactivity/irritation/disinhibition/aggression (HIDA) domain One group of symptoms that commonly co-occur in AD is the Hyperactivity/Irritation/Disinhibition/Aggression (HIDA) domain, including agitation, irritability, aggression, disinhibition and impulsivity. AD is associated with extensive serotonergic deficits in numerous brain regions that might partly explain the agitation and irritability associated with the disease [95], and deficiency of serotonin in certain brain areas has been implicated in hyperactivity [96]. Specifically, reductions in both 5-HT and its metabolite 5- hydroxyindoleacetic acid (5-HIAA) were associated with over activity in Brodmann’s Area 10 of AD patients [37]. In genetic analyses, polymorphisms in TPH2 were associated with an increase in activity disturbances and hyperactivity [97]. The 5-HTT L and S alleles have shown inconsistent results in influencing hyperactivity, with both being found to influence these symptoms in some studies but not others [82]. The 5-HTR2A T102C alleles has also had a mix of studies associating the TT genotype with decreased risk of aberrant motor behavior [83]. 5-HT has been strongly implicated in the modulation of aggression in animals and humans [98,99] and the associations between aggression and 5-HT extend to AD patients. Genetically, the presence of the 5HTT variable number of tandem repeats sequence (5-HTTVNTR) allele 10 was associated with aggressiveness [100], highlighting how differences in local serotonin concentrations may lead to aggressive behavior. In addition, the L/L polymorphism of 5-HTTLPR, a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter, was also found to be associated with aggressive behavior in AD patients [101]. Even in otherwise healthy patients, several studies have suggested that pharmacological compounds that agonize or antagonize 5-HTR1A, 1B, 2A, and 2C modulate the tendency towards aggressive behavior in rodents, guinea pigs, primates, and humans [102]. Within the 5-HTR1 subtype, agonists acting on the 5-HTR1B have more selective anti-aggressive effects in mice than those acting on

6. Psychosis domain Dysfunctional serotonergic signaling significantly correlates with psychosis in AD [37,122], but direct evidence of how serotonergic disruption in AD contributes to psychosis is unclear. A few studies reported that 5-HTR2C has been associated with delusions and hallucinations in AD patients [123,124]. Moreover, second-generation antipsychotics that target to 5-HTR2A and 2C are often prescribed to control delusions and hallucinations in AD [125,126]. In fact, psychotic symptoms, mainly delusions and hallucinations, are striking features that impact both AD patients and their caregivers tremendously [127–129]. The potential role of altered serotonin signaling in psychosis originated from the findings that several hallucinogenic compounds, such as psilocybin (the active compound in mushrooms), mescaline (the active compound in peyote), and Lysergic Acid Diethylamide (LSD), bind to activate various forms of serotonin receptors, leading to dissociation and hallucinations [130]. While such observations suggest that selective activations of serotonin systems are capable of inducing psychosis, these are “dirty drugs” that activate a number of other GPCRs, including dopaminergic receptors [128]. Though other serotonergic system proteins may be affected, 5-HTR2A 39

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Table 3 Potential role of 5-HTR subtypes in behavioral and psychological symptoms of dementia. Receptor

Associated symptoms

Changes in Alzheimer’s disease (human studies)

Changes in Alzheimer’s disease (animal studies)

5-HTR1A

↓ Raphe nuclei [62,80]

5-HTR2B 5-HTR2C 5-HTR3 5-HTR4

Aggression [102], Anxiety [94], Depression [26,62,63,78], Delusion [94] None known Anxiety [79], Depression [78,79], Apathy [121], Psychosis [125] [more in comments] Aggression [102,105] Anxiety [82], Depression [82], Psychosis [123] Anxiety [86], Psychosis [123,124] Anxiety [87], Aggression [99], Cognition [44]

5-HTR5

Hallucinations [13]

↓ Frontal, temporal [104,26], hippocampus, amygdala Unknown ↓ Frontal, temporal [82], cingulate, hippocampus, amygdala ↓ Frontal cortex [105] ↑ BNST/Amygdala [82,80] ↔ Amygdala, hippocampus [57] ↓ Frontal [44], amygdala [82], hippocampus [43] Unknown

5-HTR6 5-HTR7

Cognition [49,50,51], Anxiety [85], Depression [49] Cognition [59,60]

5-HTR1D/1E/1F 5-HTR2A

Unknown ↓ Prefrontal [79], amygdala [78], hippocampus [78] ↓ Prefrontal [102], NAc [102] [105] ↑ Prefrontal [82] ↓ Hippocampus [86], amygdala [86] ↓ Hippocampus [42], cerebrum [99] ↓ Hippocampus [13], prefrontal cortex [13] ↔ Neocortex [85] ↓ Hippocampus [60]

↓ Hippocampus [49], dorsal raphe nucleus [49] ↓ Hippocampus [59,82]

Abbreviations: NAc = Nucleus accumbens; BNST = Bed nucleus of the stria terminalis.

Fig. 2. Serotonin receptors and their bidirectional associations with BPSD.

however, that lack of genetic risk does not exclude the possibility of 5HTR alterations being involved in BPSD pathogenesis. Still, further investigation into BPSD in AD utilizing unbiased approaches such as GWAS, transcriptomics, and proteomics will hopefully reveal more interactions between these domains and the serotonergic system. Larger sample sizes and carefully designed, consistent studies are needed to understand the roles of serotonergic system in cognition and BPSD in AD. Obviously, research determining the genes and proteins that lead to BPSD in AD is still in its infancy. A more immediately accessible avenue of investigation may be to use a combined application of agonists and antagonists for defined serotonin receptors to determine if greater therapeutic benefit exists for AD when specific serotonergic drugs are used concomitantly [138]. Second generation antipsychotics are already used off-label for treating agitation, aggression, and psychotic symptoms in BPSD. However, these agents carry a Food and Drug Administration black boxed warning for increased mortality when used for dementia-related psychosis. Possibly, a combination of approaches may reduce this risk of increased mortality, though more specific antagonists and agonists may be needed in the long run. Beyond serotonin receptors and serotonin transporters, epigenetic mechanisms and functional proteomics are another rich domain for future work [19]. One potential study that may greatly move the field along would be a systematic, BPSD domain-based study, combining gene expression analysis through RNA-seq across implicated brain regions to identify alterations specific to commonly perturbed pathways, which may eventually provide enough information to make possible evidence-based, patient-specific treatments for BPSD in AD more likely

has the strongest evidence for influencing psychotic symptoms in AD. For the 5-HTR2A T102C polymorphism, the CC genotype has been associated with risk of psychotic symptoms in AD, though this positive result was not always replicated across studies [83] (Table 3, Fig. 2) 7. Discussion and conclusion The serotonergic system is one of the most studied systems in the CNS, yet we lack complete understanding of downstream mechanisms underlying the development of cognitive deficits and other BPSD in AD. As with most AD symptoms, the bulk of the evidence for serotonergic involvement in AD describes its role in modulating cognition or regulation of known AD-causing molecules, namely Aß and hyperphosphorylated tau. Still, even the interaction between the serotonergic system and cognitive deficits tend to be associative at best, and mechanistic understanding of specific 5-HTRs underlying AD symptoms with brain circuit-level resolution is lacking. Additionally, regional volumetric reductions impact the serotonergic system [131,75] as well as brain-derived neurotrophic factor (BDNF) to significant degrees [132], which are found in other neurodegenerative disorders such as Parkinson’s disease [133], frontotemporal dementia [134], and Huntington’s disease [135]. Compounding this problem is the fact that most of the genetic studies mentioned are candidate gene studies, which are often biased and utilize small sample sizes. In addition, serotonergic genes have not been implicated in GWAS studies of cognitive decline nor psychosis in AD [136,137], though this may be due to loss of statistical power caused by the multitude of unbiased comparisons across tens of thousands of genes (Table 4). It’s important to keep in mind, 40

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Table 4 Genetic studies of 5-HTRs in AD. Author, date

Subjects (N)

Study type

Target symptom(s)

Association

Holmes, 2003 [81]

AD, late-onset (158)

Depression

5-HTR2A T102C; 5-HTR2C G68C(C23S)

Flirski, 2011 [82] Tang, 2017 [83]

# articles dependent on foci 9 eligible studies (2005)

BPSD BPSD

5-HTR2C G68C(C23S) 5-HTT LPR 5HTR2A T102C

Liu, 2001 [84]

AD (145) Controls (104) AD, no anxiety (22) AD, anxiety (12) Aged Controls (n = 14) Probable AD (249)

Association study of selected SNPs in 5HTR2A/2C Systematic review Meta-analysis to investigate 5HTR2A T102C polymorphism Association study of 5-HTR6 polymorphism C267T Association study

Depression

5-HTR6 C267T

Antemortem anxiety

5-HTT LPR

Prospective, longitudinal study for candidate genes Association study

BPSD

5-HTT LPR (SLC6A4), TPH2

BPSD

5-HTT LPR, 5-HTTVNTR ApoE

Case-control study

Aggression

5-HTT LPR

Association study in Finnish founder population GWAS

Impulsivity

5-HTR2B stop codon (5 H TR2B Q20*) (exon-centric sequencing) HTR2B*rs17440378

Tsang, 2003 [85]

Engelborghs, 2013 [97] Ueki, 2007 [100] Sukonick, 2001 [101] Bevilacqua, 2010 [105] Montalvo-Ortiz, 2018 [106] Hollingworth, 2012 [136]

Sherva, 2014 [137]

Mild AD (200) (160 reached moderate AD) AD + Aggression [58] AD + No Aggression (79) Impulsive Males, unrelated (96) AAs (3269) EAs (2546) AAs, from GTP (89) AD + Psychosis (1299) AD + No Psychosis (735) Controls (5659) AD, discovery sample (303)1 AD, replication sample (323)2

Cannabis-related aggression

Combined analysis of three GWASs

Psychosis

SLC2A9*rs6834555, VSNL1*rs4038131

GWAS

Cognitive decline

SPON1*rs110231391, SPON1*rs116063452

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