Neuropsychiatric Symptoms of Alzheimer’s Disease: An Anatomic-Genetic Framework for Treatment Development

Abstract

Background:

Despite the burden on patients and caregivers, there are no approved therapies for the neuropsychiatric symptoms of Alzheimer’s disease (NPS-AD). This is likely due to an incomplete understanding of the underlying mechanisms.

Objective:

To review the neurobiological mechanisms of NPS-AD, including depression, psychosis, and agitation.

Methods:

Understanding that genetic encoding gives rise to the function of neural circuits specific to behavior, we review the genetics and neuroimaging literature to better understand the biological underpinnings of depression, psychosis, and agitation.

Results:

We found that mechanisms involving monoaminergic biosynthesis and function are likely key elements of NPS-AD and while current treatment approaches are in line with this, the lack of effectiveness may be due to contributions from additional mechanisms including neurodegenerative, vascular, inflammatory, and immunologic pathways.

Conclusion:

Within an anatomic-genetic framework, development of novel effective biological targets may engage targets within these pathways but will require a better understanding of the heterogeneity in NPS-AD.

Keywords

Agitation Alzheimer’s disease apathy behavior dementia depression genetics neuroimaging neuropsychiatric

INTRODUCTION

There are currently approximately 50 million people living with Alzheimer’s disease (AD) and related dementias worldwide with greatest prevalence in Asia [1]. By 2050, global prevalence is expected to reach more than 152 million people with 6 to 14 million in the United States [2]. As a result, the anticipated costs associated with caring for AD patients will be staggering. By 2050, it will cost the nation more than $1 trillion unless there are marked improvements in prevention and treatment [2].

Unfortunately, there had not been a new drug approved for AD since 2003 until the recent provisional FDA approval of lecanemab in (2022) and pending approval of donanemab likely in 2023 (application in review). Otherwise, over the last 20 years, there have been more than 150 failed clinical trials for disease-modifying drugs aimed at reducing the burden of amyloid-β (Aβ) in the brain. While lecanemab and donanemab have shown efficacy in decreasing amyloid burden, there have been concerns for lack of efficacy as well as development of unwanted neurological side effects such as amyloid related imaging abnormalities which may represent vasogenic edema and sulcal effusions and hemosiderin deposits. [3] It has become increasingly apparent that other biological targets need to be considered. Similarly, there are currently no approved drugs for the non-cognitive behavioral symptoms known as neuropsychiatric symptoms of AD (NPS-AD). NPS-AD represent multi-dimensional, complex behavioral constructs that broadly describe the regulation of emotion, social behavior, and thought content. They are nearly universal (80–97%), persist, and recur over time [4, 5], and are associated with high rates of patient and caregiver distress, institutionalization, and poor physical outcomes, including death [6 –8]. Pharmacologic strategies have focused on repurposing psychotropic medications approved for use in idiopathic psychiatric disorders and non-pharmacologic strategies, while considered first-line, have limited and highly variable benefits. While medications can provide symptomatic relief, they often come with significant side effects including mortality [9 –11]. Moreover, clinicians often face uncertainty in prescribing treatments for behavioral symptoms because of significant phenomenological overlap between, for example, psychosis and agitation. Similar to the cognitive symptoms of AD, candidate drug trials for NPS-AD have more frequently than not produced weak or equivocal results. An important reason why more specific therapies have failed to develop is that the underlying biological mechanisms are not well understood.

In AD research, there is steadily growing interest in understanding these complex behavioral phenotypes in terms of biological substrates. In other neuropsychiatric diseases, such as autism and schizophrenia, multi-modal neuroimaging and genomic methods are being leveraged to generate mechanistic hypotheses. In NPS-AD, insights gained from neuroimaging findings over the last 20 years have given rise to hypotheses of NPS-AD as disconnection syndromes of coherent neural networks [12 –15], while advances in genomic science have identified specific gene associations to discrete NPS-AD phenotypes. Since brain structure is an intermediate phenotype of genotypic expression, integrating neuroimaging with genetic data within a common conceptual framework may better guide future therapeutic development for NPS-AD. In this review, we present current knowledge related to biological mechanisms of NPS-AD and propose an integrated conceptual framework for discussion of current and future treatment approaches. We focus on three NPS-AD, depression, psychosis, and agitation, because of their high incidence and distress to patients and caregivers.

METHODS

A systematic literature search was conducted to identify the relevant studies. Initial searches were run on December 11, 2020 and a repeat follow-up search February 8, 2023. Using PRISMA guidelines [16], candidate studies for inclusion into this review were identified through a systematic literature search in the following databases: Medline (PUBMED), PsycINFO (EbscoHost), and EMBASE (Embase.com) from January 2000 to present for English-language articles including but not exclusive to the following search terms: “Neuropsychiatric symptoms” AND “Alzheimer’s dementia”; “neuroimaging” OR “MRI”; “Genetic” OR “genome wide association study”; “neuropsychiatric symptoms” AND “Alzheimer’s dementia” AND “treatment” OR “management.” We also searched reference lists of selected articles meeting selection criteria for other relevant studies. Initial search results were subjected to a thorough review (by authors MN, JO, JK) of the study’s abstract and consequently included studies based on the following criteria: 1) studies describe association between genetic or neuroimaging methods and NPS-AD (neuroimaging studies limited to structural CT or MRI and genetic studies limited to genetic association studies and genome-wide association studies); 2) human studies. Studies without a control group were included. Associations found within neuroimaging studies are organized by brain cortical lobar region (frontal, temporal, parietal, occipital) and generalized subcortical regions and substructures. Associations found in the genetic studies are organized by predominant functional expression, as modelled in a review paper by DeMichele-Sweet et al. [17].

RESULTS

Systematic review of the literature using indicated keywords yielded 183 articles for neuroimaging related research and 161 articles for genetic related research for a total of 344 articles screened initially. After applying inclusion and exclusion criteria, 41 neuroimaging papers and 47 gene association papers were selected for in-depth review as presented in the Supplementary Material.

Depression

Depressive symptoms include low affective state (sadness), anergia (abnormal lack of energy), verbal or behavioral expression of suicidality, guilt, or a sense of burden to caregivers or family. There were 22 neuroimaging studies of depression symptoms in AD with the largest number (12) reporting association with the frontal lobes and structures within (Table 1, Fig. 2). The anterior cingulate cortex (ACC) in particular was associated with depressive symptoms. The ACC is considered an “executive” region with subregions specific to emotion and affect, as well as cognition. Another significant function of the ACC involves modulating initiation, motivation, and goal-directed behaviors all functions that are commonly impaired in depression. Within the temporal lobe, the hippocampal formation was most notably associated with depressive symptoms. This relationship has been supported by other neuroimaging data showing selective loss of 5-HT1A serotonin receptors in the hippocampus [18]. Subcortical white matter lesions were also found to be associated with depressive symptoms but to a lesser degree than atrophic cortical changes. The presence of lesions in the basal ganglia [19, 20] and corpus collosum [21, 22] appeared to be most associated with depressive symptoms.

Fig. 1

Anatomic-genetic framework of NPS-AD.

Table 1

Neuroimaging and genetic associations with NPS-AD

	Neuroimaging		Genetics
Depression	Frontal Lobe	[88 –94]	Monoamine:
	ACC	[44 , 96]	TPH1 A218C	[26]
	Middle frontal cortex	[43]	MAOA VNTR	[26]
	Prefrontal cortex	[97]	*5-HT2A T102C and SLC6A4 5-HTTLPR [27]
	Temporal Lobe	[89 , 97]	Vascular:
	Entorhinal cortex	[95]	VCAN	[83]
	Superior temporal cortex	[98]	ANGPT4	[84]
	Inferior temporal gyrus	[98, 99]
	Medial temporal cortex	[100]	Inflammatory:
	Hippocampus	[99 , 101–103]	SIRT2	[31]
	Fornix	[22]
	Uncinate fasciculus	[22]	Immunologic:
	Fusiform gyrus	[98]	FKBP5	[26]
			*IL-1B, MTHFR	[105]
	Parietal Lobe	[88, 90]
			Neurodegenerative pathway:
			APOE	[28 , 31]
	Occipital Lobe		CHAT	[29]
	Lingual gyrus	[96]	*SORL1	[106]
	Insula	[89]	Other
			BDNF	[26 , 32–34]
	Subcortex and white matter	[90, 104]	LRFN5	[84]
	Caudate	[104]	GRM7-AS3	[84]
	Lentiform	[104]	ERK/MAPK	[84]
	Basal ganglia	[19, 20]	CR1	[107]
	Thalamus	[19]	*PER2, PER3, CLOCK,
	Corpus callosum	[21, 22]	OX2R
Psychosis	Frontal Lobe	[109, 110]	Monoamine:
	ACC	[45]	5-HT2A 102T	[121 –123]
	Orbitofrontal	[111]	*5-HT2A 102T	[124]
			5-HT2A and 5-HT2C	[125]
	Temporal Lobe	[112, 113]	SLC6A4 5-HTTLPR	[126 –129]
	Superior Temporal Gyrus	[39, 111]	COMT	[126 , 131]
	Hippocampus	[38 , 115]	DRD1 and DRD3	[132]
			DRD1 B2 allele	[133]
			*DRD3	[134]
	Parietal Lobe	[45 , 116]	Synaptic Function:
	Posterior cingulate gyrus	[39]	NRG1	[135]
	Supramarginal gyrus	[117]
			Vascular:
	Occipital Lobe	[116 , 119]	None
	Cerebellum	[39]	Inflammatory:
			IL-1B	[136]
	Subcortex and white matter:
	Basal Ganglia	[20]	Immunologic:
	Claustrum	[109]	None
	Thalamus	[39]
	Insula	[39, 41]	Neurodegenerative pathway:
	Corpus Callosum	[120]	APOE	[86 , 137–140]
			G72/DAOA	[141]
			MAPT H2 allele	[142]
			CHRNA7 T allele	[143]
			*APOE and CHAT	[144]
			*No association with neurodegenerative pathway genes	[145]
	Neuroimaging		Genetics
			Other:
			Chromosome 19q13	[146]
			BDNF	[33 , 147]
			OLIG2	[148]
			SET	[149]
			JAG2	[149]
			ZFPM1	[149]
			*TOMM40	[150]
			*NRG1	[151]
Agitation/Aggression	Frontal Lobe	[43 , 46]:	Monoamine:
	ACC	[40 , 44–46]	5-HT2A 102T	[121]
			DRD1 and DRD3	[132]
	Temporal Lobe		COMT and 5-HTTLPR	[126]
	Amygdala	[46]	COMT	[47]
	Hippocampus	[46]	DBH	[47]
			TPH	[47]
	Parietal Lobe	[45, 152]
	Occipital Lobe:		Vascular:
	None		None
			Inflammatory:
	Insula	[43]	None
	Subcortical and white matter:		Immunologic:
	None		None
			Neurodegenerative pathway:
			*SORL1	[106]
			APOE e4	[87]
			Other:
			AR	[47]
			BDNF	[47]
			NOS	[47]

*indicates no associations between NPS-AD and genes studied. Most neuroimaging associations were statistically assessed using structural atrophy as the primary measure. Both negative and positive correlations are included because the significance of this directionality is not clear as it relates to atrophy and clinical symptoms in the context of AD. In the genetic section of the table, we demarcate studies showing null associations (*). Directionality of association as well as further details in both neuroimaging and genetic studies are found in Supplementary Tables 1 and 2.

Fig. 2

Anatomical associations by NPS-AD. Graphical representation of anatomical associations by NPS-AD. Lateral view shows lobar associations and medial view show substructure associations where available. Relative size of icons represent approximate number of papers or references showing association with NPS-AD (Table 1). Substructures not visible: Amygdala, insula, hippocampal body, claustrum, lentiform, entorhinal cortex.

The association of monoamines with symptoms of depression has been well researched over the last 20 years. Serotoninergic neuronal loss in the raphe nucleus and hippocampus as well as noradrenergic loss in the locus coeruleus has been associated with depressive symptoms in AD [23 –25]. Genetic studies of depressive symptoms in AD showed variable associations with genes involved in monoamine synthesis or function (Table 1, Fig. 3). Arlt et al. [26] found a positive association between the intronic SNP rs1800532 (often referred to as A218 C) in the tryptophan hydroxylase gene TPH1. Tryptophan hydroxylase is involved in the first and rate-limiting catalytic step in the biosynthesis of serotonin. It must be noted, however, that TPH1 is the gene responsible for peripheral TPH production and TPH2 specific to the brain. They also found a variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA) that is known to be involved in depressive symptoms in AD. Michelli et al. [27], found no association between the synonymous coding variant rs6313 (often referred to as T102 C) in the serotonin receptor 2A gene (HTR2A) or the promoter repeat polymorphism in the serotonin transporter gene (SLC6A4) known as 5-HTTLPR and depressive symptoms in AD.

Associations of depressive symptoms with genes involved in the neurodegenerative pathway were found and included Apolipoprotein E (APOE) and choline acetyltransferase (CHAT) [28 –31]. (Table 1, Fig. 3) It is noted that there are rich concentrations of cholinergic neurons in medial temporal lobe structures including the hippocampus. Brain-derived neurotrophic factor (BDNF) is the most abundant and widely distributed neurotrophin in the brain. A common coding variant, rs6265, leading to a Val66Met protein change, affects the activity-dependent release of BDNF and has been associated with depressive symptoms in several studies [32 –34].

Fig. 3

Gene Associations by NPS-AD. Frequency graph of number of papers demonstrating gene associations with NPS-AD (Table 1) organized by putative gene mechanism and NPS-AD.

An important distinction to depression is apathy, which is described as a state of amotivation, loss of initiative or drive without the affective component of sadness. Apathy has been associated with the frontal-subcortical reward circuitry including the inferior temporal cortex, posterior cingulate cortex (PCC), and frontal lobe structures including the orbitofrontal cortex as well as the ACC [35].

Psychosis

AD patients with psychotic symptoms (predominantly visual hallucinations and paranoid, non-bizarre or simple delusions such as those of theft, infidelity, and abandonment) portend poorer psychosocial and physical health outcomes as well as increased rates of caregiver burnout. Additionally, the incidence of psychosis is associated with more rapid cognitive decline in AD [36, 37]. Neuroimaging results from this review show prominent associations with atrophy of the temporal and parietal lobes, and less so with frontal and occipital lobe structures and subcortical structures. (Table 1, Fig. 2) As in NPS-AD depression, increased atrophy of the hippocampus was associated with psychosis. Lee et al. found an independent association of NPS-AD psychosis with right hippocampal atrophy [38]. In addition to showing associations with the entire parietal lobe, PCC atrophy was found to be positively associated with psychosis in several studies [39, 40]. The PCC is richly interconnected with the hippocampus and posterior hippocampal gyri, posterior parietal cortex, and dorsal striatum and as such plays a key role in visuospatial cognition and memory. Fischer et al. [39] showed positive associations between PCC atrophy and psychosis in AD in a research cohort while Nowrangi et al. [40] showed a similar association in a clinical cohort based at an outpatient memory clinic. Similar to depressive symptoms (above), white matter lesions were also associated with psychotic symptoms though to a lesser degree. Most notably, lesions to the insula as shown in two papers [39, 41] were found to be associated with psychosis in AD.

The literature linking NPS-AD psychosis with genes is robust with 26 studies showing associations with the majority focusing on genes expressing some product of the monoamine synthesis pathway (Table 1, Fig. 3). Genes involved in serotonin synthesis and function are prominently seen in the literature with 9 papers showing association with NPS-AD psychosis (Table 1). Genes coding for dopamine synthesis and function (Dopamine receptors and COMT) were also associated with psychosis. In schizophrenia antipsychotic medications have been hypothesized to modulate dopaminergic function inherent to the mesolimbic and mesocortical projections and their innervations in mid-brain, basal forebrain (nucleus accumbens) and the prefrontal cortex. The mesocortical projections are of particular interest because of their associations with negative psychotic symptoms and cognition. Secondly, genes or gene products involved in the neurodegenerative pathway (APOE, MAPT, NMDA receptor genes), which are active in the synthesis and function of glutamate (NMDA) and tau (MAPT), were associated with psychotic symptoms. Interestingly, we did not find any studies associating psychosis with the core AD genes amyloid protein precursor (APP) or presenilin (PSEN1, PSEN2) genes or gene products likely because disease-causing mutations in these genes are rare. A variety of other genes including BDNF, as were seen in depression, are shown in Table 1 and have been reported in earlier reviews [42].

Agitation and aggression

Agitated and aggressive AD patients commonly present with psychomotor restlessness including stereotypic and non-stereotypic motor behavior such as pacing, verbal and non-verbal disinhibition, and other asocial or assaultive behavior. Though neuroimaging studies of these behaviors have been limited in large part because of the practical challenges of scanning agitated and uncooperative patients, several studies have shown associations between symptoms and brain structure (Table 1, Fig. 2). Hu et al. [43], through a secondary analysis of the Alzheimer’s Disease Neuroimaging Initiative dataset, found a relationship between agitation (as assessed by the Neuropsychiatric Inventory) and atrophy in the left inferior frontal/insula and bilateral retrosplenial cortices using a voxel based MRI method (VBM). Using a diffusion tensor imaging method, Tighe et al. [44] found decreased fractional anisotropy suggestive of decreased white matter integrity in the anterior cingulum bundle in mild cognitive impairment (MCI) and AD patients to be associated with agitation as well as irritability, apathy, dysphoria, and nighttime behavioral disturbances. Other studies have shown an association between atrophy of the ACC and agitation in AD [40 , 46]. In light of the ACC’s broad role in behavior, conduct, and affective regulation it likely represents a “behavioral hub” for differential networks related to several NPS-AD. Additionally, Trzepacz found an association between agitation and frontolimbic atrophy including hippocampus and amygdala in patients with MCI and AD using VBM [46].

Compared to depression or psychosis, we found few genetic studies related to agitation and aggression (Table 1, Fig. 3). The limited evidence base has reported associations with genes coding for the monoamine system, specifically dopamine and serotonin synthesis and neurotransmission. Lukiw et al. [47] found evidence of mis-regulation of a small family of genes expressed in the human hippocampus that appear to be involved in the expression of both AD and aggression: COMT, DBH, and TPH. They also found that the magnitude of expression was greater in later stages of AD and that these genes were also implicated in the onset and/or propagation of schizophrenia.

Current treatment approaches

First, it should be noted that non-pharmacological treatments (NPT) are considered first-line approaches to NPS-AD, especially in the absence of effective or approved medications. NPTs may include such interventions as cognitive stimulation, exercise, music, multi-sensory, and tactile stimulation for patients with dementia. Though not discussed in this review, NPT have been recently linked to physiological mechanism even if not explicitly related to brain structure or genes. As an NPT for NPS-AD, exercise has been the best studied. Matura et al.’s review of the effect of exercise on NPS-AD found a positive effect on reducing NPS [48]. From this review, the authors postulated that increased monoaminergic and neurotrophin levels, as well as increased immune activation were likely mechanisms for the measured effects. Further, a randomized controlled trial of a combined cognitive and physical training program in MCI showed a significant decrease in NPS and increase in quality of life in the intervention group compared to the standard care group [49]. Music therapy [50] and massage therapy [51] as well as the effects of tending to an indoor therapeutic garden [52] were all studied and have been shown to provide positive yet short-lived effects.

Depression

The first-line treatment of depressive symptoms in AD has been antidepressant medications, specifically serotonin selective reuptake inhibitors (SSRI). A meta-analysis by Sepehry et al. [53] and a review by Pomara and Sidtis [54], however found non-significant effects in two depression nested analyses assessed using standardized depression scales. Additionally, a large multi-center trial (Depression in Alzheimer’s Disease-2 or DIADS-2) found no advantage to sertraline over placebo in individuals with depression and AD [55 –57]. Despite this, SSRIs are clinically favored for their perceived effectiveness and side effect profile over other antidepressants such as tricyclic antidepressants, (because of their anticholinergic effects) monoamine oxidase inhibitors, and other drugs with mixed neurotransmitter function.

Psychosis

Relief from psychotic symptoms in patients with AD has primarily been addressed by use of antipsychotic medications even though the FDA has given a “black-box warning” of increased mortality [58, 59]. Though the CATIE-AD trial showed non-significant treatment outcome (all-cause discontinuation) of three antipsychotics (olanzapine, quetiapine, risperidone) compared to placebo [60, 61], more recent analyses showed that treatment with risperidone showed greater improvement on the Clinical Global Impression of Changes (CGI-C) scale [62]. Pimavanserin, an inverse agonist and antagonist at the 5-HT2A and 5-HT2 C serotonin receptors was originally approved in 2016 for the treatment of Parkinson’s disease psychosis. Recently, it has recently shown positive outcomes for treatment in AD psychosis in an early phase III clinical trial (HARMONY; NCT03325556) [63]. In a separate recent randomized, double-blind, placebo controlled trial of pimavanserin in AD nursing home residents those with severe psychosis showed large treatment effects (delta = –4.43, Cohen’s d = –0.73, p = 0.011) of improved psychosis at the > 30% (88.9% versus 43.3%, p < 0.001) and > 50% (77.7% versus 43.3%, p = 0.008) levels between pimavanserin and placebo groups respectively [64]. Therefore, this evidence suggests that use of antipsychotic medications for NPS-AD psychosis may be effective but should cautiously consider important risks in the greater context of the patient’s general health and that newer antipsychotic medication targeting mechanisms other than dopaminergic neurotransmission may also be useful. Novel antipsychotic mechanisms such as serotonergic and dopaminergic partial agonism may be systems of interest in developing novel agents with antipsychotic action. Additionally, cholinergic and noradrenergic systems may also be considered as alternate mechanisms with potential benefits in NPS-AD. There has been recent growing interest in studying these mechanisms [65 –67] because of their role in adaptive cognition and behavior but further research is needed to establish tolerability and efficacy as well as considering a personalized approach to biobehavioral symptom management for NPS-AD.

Agitation and aggression

Possibly because of the large overlap in clinical presentation with psychotic symptoms, antipsychotic use for agitated and aggressive symptoms has been the first line treatment. However, the literature is not of sufficient quantity or quality to fully support their use. The Citalopram for Agitation in AD (CitAD) study [68] found considerable heterogeneity in clinical response of agitation to citalopram at 30 mg/day despite the fact that there was overall significant reduction in agitation and caregiver distress. Studies of dopamine augmentation [69] with amantadine have only shown modest effects [70]. Recently, a randomized, double-blind, placebo-controlled trial (NCT01862640; NCT01922258) was conducted of brexipiprazole, a serotonin-dopamine activity modulator that acts as a partial agonist at serotonin 5-HT2A and noradrenaline α1B/α2 C receptors. Results of this trial showed a greater numerical improvement on the Clinical Global Impression of Severity (CGI-S) scale in patients titrated to 2 mg/day dose compared to similarly titrated placebo patients in post-hoc analysis. Mood-stabilizing anticonvulsants such as valproic acid, dextromethorphan/quinidine, and other novel agents are being currently investigated but results have not been consistent.

Novel approaches

There growing interest in exploring the use of novel drug classes for NPS-AD. The endocannabinoid system has garnered growing interest from patients, clinicians, and scientists alike. Mechanistically, cannabinoids such as tetrahydrocannabinol (THC) are agonists of the CB₁ and CB₂ receptors and produce psychotropic effects. However, in a recent meta-analysis, Ruthirakuhan et al. found that, as a class, natural cannabinoids did not reduce agitation as well as synthetic cannabinoids such as dronabinol and nabilone though the studies were often under-powered and lacked appropriate comparison groups [71]. Unlike THC, cannabidiol (CBD) is a non-psychomimetic compound that has also rapidly gained interest recently but was used in the 1970 s for the treatment of epilepsy. CBD exerts its action through a variety of proposed CNS mechanisms including modulation of 5HT receptors, GABA, the endocannabinoid anandamide, and other neurochemical systems. There are currently no known human clinical trials using CBD.

Non-invasive and minimally-invasive brain stimulation therapies are a growing area neuroscientific and clinical interest. Repetitive transcranial magnet stimulation (rTMS) and transcranial direct current stimulation (tDCS) are young technologies in their application to NPS-AD, but their early appeal includes favorable side-effect profile as well as the ability to target functional brain networks. Vacas et al. [72] systematically reviewed brain stimulation treatments on NPS-AD. Seven randomized controlled trials showed that rTMS had statistically significant benefits in the reduction of NPS-AD. Though literature is limited, preliminary and exploratory evidence suggest that brain stimulation technologies may be a viable option in the treatment of NPS-AD.

DISCUSSION

Proposed framework for discussion of current and future treatment approaches

In this systematic review, we attempt to understand targets for potential NPS-AD treatments by using the neuroimaging and genetic literature to uncover underlying mechanisms. The growing field of imaging genetics seeks to use anatomical or physiological imaging technologies as phenotypic assays to evaluate genetic variation, thus combining both approaches. While there has been an effort to use imaging genetics to explore anatomic-gene relationships in aging and cognition [73], this approach has not been applied well to NPS-AD. Our literature search, then, approximated an imaging-genetics approach and our findings infer such a significance. It is hoped that understanding the dynamic between genes and structure will aid the development of targeted and individualized therapies for symptoms such as depression, psychosis, and agitation and aggression of AD.

First, we aimed to identify individual NPS-AD rather than symptom clusters or subsyndromes of NPS to more precisely elucidate symptom-anatomy and symptom-gene relationships. We acknowledge, however, that previous research in NPS-AD has used factor analytic methods to generate symptom clusters of individual NPS [74 –76]. One recent example of cluster generation from Cheng et al. [77] supported a four-factor model: 1) behavioral problems (agitation/aggressiveness, disinhibition, irritability, and aberrant motor behavior); 2) psychosis (delusions and hallucinations); 3) mood disturbance (depression, sleep, appetite, and apathy), and 4) euphoria. While this approach has represented an advancement in the nosology of these symptoms, research utilizing cluster models has been inconsistent and the presence of contradictions within the available data continue to be limitations [78]. As this nosology continues to mature, future research may better incorporate and may be better suited to use symptom clusters for associations between complex genetic relationships, e.g., poly-gene interactions and anatomical associations involving functional networks.

Results of this literature review, then, have revealed several interesting and important findings. First, we found that in all three symptom types, associations have been found primarily between atrophy in structures of the frontal, temporal, and parietal lobes and between NPS and genes involved in monoamine biosynthesis and neurotransmission. Atrophy in ACC, PCC, and hippocampus were found to be most associated with several NPS-AD. These fronto-limbic structures are generally considered as heteromodal association cortices with a large degree of interconnectivity to other cortical and subcortical structures. Likely forming distributed networks, these interconnected regions integrate emotion, sensory, and motor responses that would be associated with the multidimensional nature of complex behaviors [12]. While not discussed here in detail, disruptions to large-scale functional networks such as the default mode network, salience network, and the central executive network have been implicated in NPS-AD [35 , 79–82] and may provide a promising platform for further investigation into the pathophysiology of NPS-AD. Methodological limitations of resting state fMRI including replicability of findings, however, will need to be addressed in order for reliable associations to be considered. Genes coding for largely regulatory monoamine synthesis and function (specifically dopamine and serotonin) as well as genes involved in the neurodegenerative pathway including the synthesis and neurotransmission of acetylcholine, tau, and glutamate were associated with NPS-AD. There is a clear connection between the anatomical locations of the neuroimaging findings and the neuronal projections of serotonin and dopamine where fronto-limbic regions contain high concentrations of neurons responsible for this function. Associations between subcortical white matter lesions and depression and psychosis were also found but to a lesser degree in the literature and no associations were found in agitation/aggression. Consideration of the anatomy, genes, and function in each of the NPS-AD in a common framework could help uncover novel targets for therapeutic development (Fig. 1).

Conclusions and future directions

We have proposed a rational anatomic-genetic framework on which to build future treatment development for NPS-AD. The neuroimaging and genetic literature support brain mechanisms underlying monoaminergic biosynthesis and function as well as brain regions (ultimately networks) and genes affected by or involved in neurodegeneration. Current treatment approaches are in line with this mechanistic understanding; however, the effectiveness of the repurposed medications has been suboptimal. Therefore, there is a disconnect between target mechanism and clinical effect. One reason for this is that other mechanisms outside of neurodegeneration and the monoamine systems may be involved. As an example, for NPS-AD depression, genes involved with neurovascular function (VCAN [83] and ANGPT4 [84]) as well as inflammatory [31] and immunologic cascade [26] have also been reported. These other mechanisms have not been as well researched and may prove to be promising targets for future development. Secondly, it should be noted that targeting single mechanisms is not likely to address the complexity inherent in behavioral syndromes and certainly the underlying anatomy of distributed networks would be evidence of that. Combination or “cocktail” approaches for the treatment of cognitive symptoms of AD are gaining interest. Combination of anti-amyloid, anti-tau, anti-inflammatory, and other mechanisms are being considered in cognition and should also be considered in NPS-AD. Finally, we must acknowledge the fact that each individual with AD is unique. Sorting out the heterogeneity of clinical symptoms in AD is a developing area in precision medicine. It is likely that in NPS-AD, a similar type of heterogeneity exists especially in areas where symptoms overlap clinically, such as depression and apathy or psychosis and agitation. As discussed earlier, utilizing symptom subdomains or clusters may be a useful method of addressing this heterogeneity in future research. Additionally, ancestry/race and sex as a biological variable are complex genetic-social constructs that also need to be considered in the further study of NPS-AD. Most genetic studies have been conducted on individuals of European ancestry. A 2009 analysis revealed that 96% of participants in genome-wide association studies were of European decent and though that percentage has improved to include 20% non-European subpopulations, most of those studies were conducted on individuals of Asian ancestry [85 –87]. As these constructs are associated with differences in phenotypic expression of underlying gene-environment interactions, future research will need to capture the genetic diversity of race/ethnicity as well consider sex. Developing individualized treatment will benefit from an anatomic-genetic framework as analysis of larger datasets may reveal distinct clinical, social, genetic, and anatomic subtypes that may respond more effectively to one treatment (pharmacological or non-pharmacological) regimen than another. As a result, opportunities for future therapy in AD and NPS-AD need to be based on a sound conceptual foundation. We hope that this framework will help evaluate past therapies and help develop the next.

Footnotes

ACKNOWLEDGMENTS

The authors would like to thank the Johns Hopkins Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease for its support and guidance.

FUNDING

The authors have no funding to report.

CONFLICT OF INTEREST

Dr. Lyketsos received payments as consultant or advisor: Astra-Zeneca, Glaxo-Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen, Orion, Otsuka, Servier, Astellas, Roche, Karuna, SVB Leerink, Maplight, Axsome.

Dr. Rosenberg has funding from the National Institute on Aging, Alzheimer’s Association, Lilly, Functional Neuromodulation (FNMI), Lilly, Alzheimer’s Disease Cooperative Study (ADCS), Alzheimer’s Disease Trials Research Institute (ATRI), Alzheimer’s Clinical Trials Consortium (ACTC), and received consulting fees from GLG, Leerink, Otsuka, Avanir, ITI, IQVIA, Food and Drug Administration, Cerevel, Bioxcel, and Sunovion, all outside the submitted work. He owns stock in Alector Inc.

All other authors have no conflict of interest to report.

DATA AVAILABILITY

Data sharing is not applicable to this article as no datasets were generated or analyzed during this study.

The supplementary material is available in the electronic version of this article: .

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