Brain tissues were used in accordance with the institutional review board (IRB)/ethical guidelines at the Louisiana State University Health Sciences Center (LSUHSC) and the donor institutions, and CERAD/NIH criteria were used to categorize all AD tissues in accordance with established guidelines (Cui et al., 2005, 2010; Lukiw et al., 2008; Montine et al., 2016). We used mRNA expression profiles and DNA-array data from a study of 12 mild-cognitively impaired (MCI) subjects (N = 12) and their controls (N = 12), and 12 age-matched sporadic AD hippocampal CA1 (N = 12) and their controls (N = 12). DNA array data was performed using state-of-the-art microfluidics hybridization platforms through an ongoing collaboration with Drs. Cristoff Eicken, Chris Hebel, Jason Mulcahey and Kyle Navel at LC Sciences (Houston, TX, USA); mRNA expression profiles and trends were independently corroborated and verified using RT-PCR or Northern blotting in previously published work from this lab (Cui et al., 2005, 2010; Lukiw et al., 2008; Bhattacharjee et al., 2016). Both the MCI and AD groups had their own control groups because of the age-differences between MCI and AD and our understanding that age is the most significant risk factor for the development of AD (Table 1). All control, MCI and AD samples had the incidence of disease verified by post-mortem evaluation; there were no significant differences in age, gender, drug history, total RNA yield, RNA quality, RNA integrity numbers (RIN) amongst the three groups (see Table 1).

The data derived from our DNA/mRNA transcriptomic array analysis were correlated and compared with those of a very recent article by Fernàndez-Castillo and Cormand (2016) who studied aggressive behavior in humans through the analysis of genes and pathways identified via candidate gene association and/or genome-wide association studies (CGAS, GWAS). Only genes of the highest significance, either up-or-down-regulated, were selected for further study, analysis and interpretation. Just six genes were found to most significantly overlap in the incidence of AD and aggression and these included the androgen receptor (AR; chrXq12), brain-derived neurotrophic factor (BDNF; chr11p14.1), catechol-O-methyl transferase (COMT; chr22q11.21), neuronal specific nitric oxide synthase (NOS1; chr12q24.22), dopamine beta-hydroxylase (DBH chr9q34.2) and tryptophan hydroxylase (TPH1, chr11p15.1 and TPH2, chr12q21.1; Figure 1).

Circulating sex steroidal hormones such as testosterone that play overlapping roles in cognition and aggression have been widely implicated in the etiopathology of AD. While the AR is abundantly expressed in both sexes, in AD expression of the AR has been found to be generally down-regulated, especially in aging males (Butchart et al., 2013; Dart et al., 2013; Fedotova et al., 2016; Jia et al., 2016). Interestingly the steroid-hormone testosterone-activated transcription factor-signaling AR (ANDR) is known to exert regulatory effects on synaptic plasticity and improve cognitive deficits in AD patients and transgenic rodent models for AD (TgAD) but the underlying mechanisms of androgenic action on cognitive performance remain unclear. Testosterone, via the AR, increases synaptophysin expression and improves synaptic plasticity and cognitive metrics in both Aβ42 peptide-hippocampal injected male rats and in the senescence-accelerated mouse prone 8 (SAMP8) TgAD murine model (Huo et al., 2016; Jia et al., 2016). In a recent double-blind, placebo-controlled, between-subject designed study, exogenous administration of testosterone to healthy adult men potentiated the AR-enriched hippocampus, amygdala and hypothalamus—anatomical regions known to be involved in the stimulation of aggressive behavior (Carré et al., 2016). Several studies have further suggested that new treatments targeted toward preventing synaptic pathology in AD or in TgAD models may involve the use of androgen agonists and/or AR-acting drugs (Jia et al., 2016; Pan et al., 2016). Interestingly, polyprenol bioregulators such as Ropren (already used in AD treatment in Russia and Australia) and polyprenol 2,3-dihydro derivatives known as “dolichols” in gonadectomized rodents exhibit decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratios in the hippocampus compared with DA and serotonin (5-HT) levels, and are associated with increased anxiolytic (antianxiety) behaviors in treated animals (Sugden et al., 2009; Fedotova et al., 2016). Therefore it may be able to design useful drugs that are able to negate aggression while promoting other useful aspects of testosterone and AR signaling including improvement in cognitive function.

BDNF is the most widely distributed neurotrophin in the human CNS and plays several pivotal roles in neural development, survival, synaptic plasticity and cognition. This 247 amino acid neurotrophin participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology, is a master regulator of synaptic plasticity and thus plays a key role in memory formation and storage (Faria et al., 2014; Nagata et al., 2014, 2016; Song et al., 2015). Therefore, the involvement of BDNF in dementia has been extensively investigated, and several reports indicate that BDNF expression is decreased in hippocampus and neocortex of AD brains (Figure 1; Peng et al., 2005; Song et al., 2015). Interestingly, children with severe autism and aggression over-express the AD-relevant beta-amyloid precursor protein (βAPP) at two or more times the levels of children without autism and up to four times more than children with mild autism; βAPP-derived Aβ peptides can directly inhibit the proteolytic conversion of BDNF from pro-BDNF thus reducing its levels (Sokol et al., 2006; Tanila, 2017). Aβ peptides indirectly affect BDNF signaling at synapses by interfering with its axonal transport in part via interaction with the TrkB receptor (Durany et al., 2000; Tanila, 2017). That BDNF expression is associated with multiple independently-regulated promoters suggest that this unique genomic structure may provide flexibility to regulate BDNF signaling in distinct cell types and circuits that serve distinct molecular functions some of which may be involved in aggressive behaviors (Spalletta et al., 2010; Faria et al., 2014; Maynard et al., 2016). It is interesting to speculate that episodic or oscillatory forms of BDNF expression in AD may correlate with aggressive outbreaks or contribute to them via complex neurotrophic signaling pathways that are known to impact behavioral phenotype.

COMT catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters DA, epinephrine and norepinephrine, resulting in one of the major degradative pathways of the catecholamine transmitters. COMT appears to play a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters such as DA in the prefrontal cortex which are involved in working memory and executive functioning (Serretti and Olgiati, 2012). Similarly, COMT and DBH are directly involved with DA metabolism; this neurotransmitter system appears to be specifically targeted by the AD process (Martorana and Koch, 2014). While levels of COMT in sporadic AD appear to be highly variable, either up- or down-regulated, meta-analysis studies have identified a possible association between AD and the COMT Val158Met polymorphism in Asian but not in European populations (Lee and Song, 2014; Sauerzopf et al., 2017). More recent and comprehensive meta-analysis involving a review of 10 independent studies, which contained a total of 2777 AD cases and 2829 controls indicated that the COMT Val158Met polymorphism is associated with a decreased risk of AD in the Asian population, but not in the Caucasian or overall populations (Yan W. et al., 2016). Interestingly, genetic risk score based on the accumulation of multiple risk alleles in BDNF, COMT and APOE for AD combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms (Wollam et al., 2015). As for other neurotrophins and neurotransmitters such as NOS1, periodic fluctuations in COMT expression in AD may correlate with aggressive behaviors and contribute to “behavioral dys-homeostasis” via complex and highly interactive neurotrophic signaling pathways that contribute to NPS events (Perroud et al., 2010; Clelland et al., 2016). Interestingly, prefrontal and temporal lobe dysfunction and mutations in the COMT gene have been linked to agitation and aggression in patients with schizophrenia, and deficits in cognitive function predispose patients with AD to agitation (Sachs, 2006; Clelland et al., 2016; Yan P. et al., 2016; Yan W. et al., 2016).

Dopamine beta-hydroxylase (DBH), an oxidoreductase belonging to the copper-requiring type II, ascorbate-dependent monooxygenase family and present in the synaptic vesicles of postganglionic sympathetic neurons exists in both soluble and membrane-bound forms, depending on the absence or presence, respectively, of a signal peptide (Herrmann et al., 2004; Godar and Bortolato, 2014; Ross et al., 2015; Godar et al., 2016). DBH converts DA to norepinephrine (Ross et al., 2015). Like COMT and NOS1, DBH exhibit wide inheritable inter-individual variability in AD that is under genetic control (Figure 1; Mustapic et al., 2013; Ross et al., 2015). Decreases in DBH activity found in the early stages of AD may be a reflection of loss of noradrenergic (NA) neurons, and the treatment of early AD patients with selective NA reuptake inhibitors may be indicated in early stages of AD to compensate for loss of NA activities (Mustapic et al., 2013). The highly complex and interactive nature of neurotrophins and neurotransmitters in aggressive behaviors are underscored by recent observations that serotonin and DA interactions in the prefrontal cortex, along with other biological factors such as norepinephrine and testosterone have been found to contribute to the aggressive phenotype, as has monoamine oxidase A (MAOA) that catalyzes the degradation of brain serotonin, norepinephrine and DA (Haavik et al., 2008; Godar et al., 2016).

NOS1, a family of NO synthases which synthesize NO from L-arginine is a pivotal mediator in neurotransmission, spatial learning and cognition and has been repeatedly implicated in the neurotoxicity associated with stroke and neurodegenerative disease (Wultsch et al., 2007; Freudenberg et al., 2015; Austin and Katusic, 2016; Miszczuk et al., 2016; Wang et al., 2016). Interestingly, NO is a gaseous neurotransmitter that has also been implicated in a wide range of pathological behaviors including aggression, anxiety, depression and cognitive functioning. NOS1 knockdown mice display a characteristic behavioral profile consisting of reduced anxiety and aggression and impaired cognitive metrics including learning and memory (Wultsch et al., 2007; Miszczuk et al., 2016; Zhou et al., 2016). Recent studies have shown that deficits of endothelial NOS1 in AD play an important role in the phosphorylation of the AD-related lesion tau in murine APP/PS1 TgAD models (Austin and Katusic, 2016) while increased NOS-1 activity and NO transmission in the hippocampus was evidenced to modulate aggression (Miszczuk et al., 2016; Zhou et al., 2016). Again, the seemingly multiphasic bioavailability of NOS1 like that for COMT provides an equally oscillatory potential for episodic and complex behaviors such as aggression against a background of the inflammatory neurodegeneration and disorganized thinking that in part characterize cognitive disruption in AD.

TPH catalyzes the first and rate limiting step in the biosynthesis of the monoamine hormone, neurotransmitter and neuromodulator serotonin (3-(2-aminoethyl)-1H-indol-5-ol, 5-hydroxytryptamine; 5-HT). Remarkably, about 90% of the human body’s total serotonin (and hence TPH biosynthetic systems) are located in the neuroendocrine entero-chromaffin cells in the human gastrointestinal (GI) tract, where it is used to regulate intestinal movements and participate in GI-neural tract signaling; the other 10% is synthesized by serotonergic neurons of the CNS where it functions in the regulation of neurite outgrowth, somatic morphology, growth cone motility, synaptogenesis, and control of dendritic spine shape and density, and behaviorally anger, aggression, mood, body temperature, appetite, sleep, pain and cognition. Serotonin acts via a heterogenic receptor family that includes G protein-coupled receptors and ligand-gated ion channels (New et al., 1998; Craig et al., 2004; Shearer et al., 2016; Wirth et al., 2016). TPH is encoded by two separate enzymes: TPH1 produces serotonin in the pineal gland and entero-chromaffin cells, while TPH2 produces serotonin in the Raphe nuclei of the brain stem and myenteric plexus. Interestingly, serotonin is phylogenetically the oldest neurotransmission system present involved in cognition and memory in both vertebrate and invertebrate species, and pathological alterations in 5-HT metabolism and/or down-regulation of serotonergic signaling have been associated with various pathophysiological conditions in the CNS including amyloidogenesis and SP formation, hyper-phosphorylation of tau and NFT formation, two classical aggregates that in part characterize AD brain neuropathology (McClam et al., 2015; Panza et al., 2015; Butzlaff and Ponimaskin, 2016; Wirth et al., 2016). Due to the extensive serotonergic denervation observed in AD and the important roles played by serotonin in both behavior and cognition, this neurotransmitter system has become a focus of dedicated research efforts to identify novel pathways in Aβ peptide or NFT assembly and/or aggregation (Butzlaff and Ponimaskin, 2016; Schneider et al., 2016; Wirth et al., 2016). Serotonin has been found to increase by 4-fold, respectively in AD raphe cell bodies over controls, while in amygdala synaptic terminals 5-HT was decreased to 0.4-fold in the same AD cases; the accumulation of TPH and its products in the raphe perikarya in AD as the result of diminished transport of TPH to axon terminals and the accumulation of oxidative metabolites of serotonin may contribute to the degeneration of serotonergic neurons in AD (Burke et al., 1990; Wirth et al., 2016). Recent studies have also shown that the administration of selective serotonin reuptake inhibitors (SSRI) to Tg-AD murine models both reduces the production of toxic Aβ peptides and SP formation (Sheline et al., 2014; Butzlaff and Ponimaskin, 2016). For example, SSRI such as the antianxiety/ antidepressant citalopram hydrobromide (Celexa) has been used in AD with varying success while antipsychotics remain the pharmacological agents with most evidence to support their use (Gallagher and Herrmann, 2015). On the other hand other recent investigations, as part of the recent Citalopram for Agitation in Alzheimer Disease (CitAD) study, indicate that higher doses of SSRIs such as citalopram actually may trigger aggression especially in patients with more severe cognitive impairment encountered in the more advanced stages of AD (Schneider et al., 2016).

With a median incidence of 152 cases/M (million) persons (range 77–430 cases/M; c.i. 80%), schizophrenia is a relatively common and perplexing neurological disorder characterized by a series of NPSs that include abnormal psychosocial behavior, anxiety, disorganized thinking and impaired cognition, reduced social engagement and emotional expression, lack of motivation and a significantly increased incidence of aggression (McGrath et al., 2008; Soyka, 2011; Morris et al., 2015; Agarwal et al., 2016; Cocchi et al., 2016; Janoutová et al., 2016; Nowak et al., 2016). Globally, there are an estimated ~25 million cases of schizophrenia; males are more often affected than females (at a ratio of 1.4 to 1), environmental and lifestyle risk factors include birth in a winter month, at a high latitude, and in an urban setting, and societal problems, such as long-term unemployment, poverty, and homelessness are common (Agarwal et al., 2016; Janoutová et al., 2016; Nowak et al., 2016; van de Leemput et al., 2016). The average life expectancy of people with schizophrenia is ~10–25 years less than the average, and in the US an estimated 16,000 people die from behaviors related to, or caused by, schizophrenia each year (Agarwal et al., 2016; Janoutová et al., 2016; Nowak et al., 2016; van de Leemput et al., 2016). As with AD, aggressive acts committed by patients with schizophrenia are a major public health concern affecting patients, their families and caregivers as well as organized healthcare and the criminal-justice system. Also similar to AD, schizophrenia appears to target high-level processing functions associated with the neocortex and cortical synaptic connectivity; the genetic contributions to schizophrenia are complex and multifactorial with the integrated contributions of brain genes thought to be centrally involved in auditory processing, altered mood and behavior, anxiety and disorganized thought (Coyle et al., 2016). As previously mentioned, five of these six genes (AR, BDNF, COMT, DBH, NOS1) identified to be dysregulated in this study in AD and aggression have been implicated in the development, onset and/or propagation of schizophrenia. Interestingly both “dopaminergic and serotoninergic hypotheses for schizophrenia”, involving an elevated genetically-based capacity for striatal increased L-phenylalanine- and/or L-tyrosine-derived DA biosynthesis, altered DA release and defects in the tryptophan-derived serotonin (5-HT) and the serotonin receptor, transporter and synaptic vesicle trafficking systems have been implicated in several of the longest held pathoetiologic- and pathogenic-hypotheses for schizophrenia (Zhang et al., 2014; Baou et al., 2016; Cocchi et al., 2016; Egbujo et al., 2016; Garay et al., 2016; Howes et al., 2017). The overlapping participation of dopaminergic and serotoninergic pathways, especially with DA-metabolizing COMT pathways and serotonin (5-HT) reuptake inhibitors (SSRIs; Zoloft, Paxil, Prozac and other antidepressants) and blockage of serotonin transporter activities are remarkable. The duality of DA and serotonin signaling is further underscored by the actions, for example, of antipsychotic medications such as Brexpiprazole (Rexulti^®; Lundbeck, Otsuka Pharmaceutical), a partial agonist at DA D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors, recently approved by the US Food and Drug Administration (US-FDA) for the treatment of acute or advanced cases of schizophrenia (McEvoy and Citrome, 2016). Such dual-action antipsychotic medications have shown positive outcomes, such as the significant reduction of relapse in patients, in two independent Phase 3 randomized controlled clinical trials for schizophrenia, and Phase 3 trials are ongoing in patients with the aggressive behaviors associated with AD (Marder et al., 2016; McEvoy and Citrome, 2016).

Of related interest is the concept of “retrogenesis” as it pertains to AD and schizophrenia. Retrogenesis predicts that: (i) brain functions decline in the opposite order to which they develop in humans or during evolution; and that (ii) these anatomical regions of the brain that developed last may be the first to deteriorate with the onset and propagation of NPS illness. Put another way, the expression of genes within anatomical regions known to direct high-level brain processing functions, such as the integration of visual, auditory and other sensory information associated with intellectual abilities, behavior, memory and cognition are: (i) not only especially vulnerable to the pathoetiology and pathobiology of schizophrenia or the AD process; but (ii) are the same brain regions that display a widespread loss of cortical synaptic connectivity driven by multiple risk genes that adversely affect synaptogenesis and synaptic integrity resulting in aggressive behaviors, such as those periodically encountered in AD (Ashford and Bayley, 2013; Douaud et al., 2014; Coyle et al., 2016).