Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

Some recent studies show promising results with galantamine in cases of drug abuse (opioids, cocaine, and cannabis) [147,148] and TBI [149]. In combination with CDP-Choline, memantine, and antipsychotics, galantamine might be useful in schizophrenia [150,151].

Rivastigmine
Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BuChE; EC 3.1.1.8) in AD [152,153]. APOE, APP, CHAT, ACHE, BCHE, CHRNA4, CHRNB2, and MAPT variants may affect rivastigmine pharmacokinetics and pharmacodynamics. CYP enzymes are not involved in the metabolism of rivastigmine [120,138,145,154]. UGT2B7-PMs show higher rivastigmine levels with a poor response to treatment [155]. In combination treatments with memantine, carriers of CYP2D6*3, UGT2B7, and UGT1A9*5 variants show differential responses to treatment. Two SNPs on the intronic region of CHAT (rs2177370 and rs3793790) [156] and CHRNA7 variants may influence the response to AChEIs [157]. Two SNPs, one intronic marker in PRKCE-rs6720975 and an intergenic NBEA-rs17798800 marker, might also contribute to differential therapeutic response to AChEIs [158]. Females with the BChE-wt/wt show a better benefit with rivastigmine than males, and BChE-K* male carriers show a faster cognitive decline than females [159]. AD patients harboring the BChE K-variant (rs1803274), causing a reduced enzyme activity, show low clinical response to rivastigmine. The K-variant (p. A539T) and other SNPs located outside the coding sequence in 5'UTR (rs1126680) and/or intron 2 (rs55781031) of the BCHE gene are responsible for reduced enzyme activity and poor response to rivastigmine [160].
Rivastigmine may be useful in VD and Parkinson's disease [161,162] and in combination with low-dose quetiapine can improve psychotic symptoms in LBD [163].
Memantine can be used alone or in combination with AChEIs in AD [168,169]. Proteomic studies in the hippocampus and the cerebral cortex of AD-related transgenic mice (3× Tg-AD) treated with memantine revealed alterations in the expression of 233 and 342 proteins, respectively [170]. In APP23 transgenic mice with cerebral amyloid angiopathy (CAA), memantine reduces cerebrovascular Aβ and hemosiderin deposits by enhancing Aβ-cleaving IDE expression [171].
Memantine is useful for the treatment of both cognitive deterioration and BDs in AD and other forms of dementia [172,173]. AD patients treated with memantine plus citalopram show improvement in BDs [174]; in combination with antipsychotics, it may improve verbal memory, learning, verbal letter fluency, and working memory with no effect on psychotic symptoms in patients with chronic schizophrenia [175,176]; at a dose of 20 mg/day, it may be effective in patients with obsessive-compulsive disorder [177]; at 10 mg/day, it may be helpful in migraine [178]; and, in combination with naltrexone, it enhances the efficacy of naltrexone in reducing alcohol drinking and craving [179]. Memantine might also be useful in the treatment of punctate and dynamic allodynia by the blockade of the microglia Kir2.1 channel to suppress microglia activation [180], and in combination with dextromethorphan, it may be beneficial in neuropathic pain [181].
In linkage disequilibrium with and adjacent to the APOE locus (19q13.2) is the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of Aβ and other proteins into mitochondria. A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene has been implicated in AD pathogenesis and PGx. The number of "T"-residues in the rs10524523 ("523") locus differentiates 3 allele groups: "short" (S, T ≤ 19), "long" (L, 20 ≤ T ≤ 29), and "very long" (VL, T ≥ 30). rs10524523 L variants are associated with a higher risk for late-onset AD (LOAD). APOE-TOMM40 interactions affect the risk of AD and the response to drugs. The S/VL and VL/VL TOMM40 poly T genotypes interact with all APOE genotypes; however, the APOE-4/4-TOMM40-L/L association is unique, accounting for 30% of APOE-4/4 carriers. TOMM40 poly T-S/S carriers are the best responders, VL/VL and S/VL carriers are intermediate responders, and L/L carriers are the worst responders to treatment. TOMM40-L/L and S/L carriers in haplotypes with APOE-4 are the worst responders to treatment. TOMM40-S/S carriers and, to a lesser extent, TOMM40-S/VL and TOMM40-VL/VL carriers in haplotypes with APOE-3 are the best responders to treatment. The TOMM40-L/L genotype is exclusively associated with the APOE-4/4 genotype in 100% of the cases, and this haplotype (4/4-L/L) might be responsible for premature neurodegeneration and consequent early onset of the disease, a faster cognitive deterioration, and a limited response to conventional treatments [4,116] ( Figure 5).
with obsessive-compulsive disorder [177]; at 10 mg/day, it may be helpful in migraine [178]; and, in combination with naltrexone, it enhances the efficacy of naltrexone in reducing alcohol drinking and craving [179]. Memantine might also be useful in the treatment of punctate and dynamic allodynia by the blockade of the microglia Kir2.1 channel to suppress microglia activation [180], and in combination with dextromethorphan, it may be beneficial in neuropathic pain [181].
TOMM40-S/VL and TOMM40-VL/VL carriers in haplotypes with APOE-3 are the best responders to treatment. The TOMM40-L/L genotype is exclusively associated with the APOE-4/4 genotype in 100% of the cases, and this haplotype (4/4-L/L) might be responsible for premature neurodegeneration and consequent early onset of the disease, a faster cognitive deterioration, and a limited response to conventional treatments [4,116] (Figure 5). Epigenetic factors are important in AD pathogenesis and response to treatment [5,26,57,61,65,71]. Sirtuin variants may alter the epigenetic machinery, contributing to AD pathogenesis. The SIRT2-C/T genotype (rs10410544) (50.92%) has been associated with AD

Psychotic Disorders
Psychotic symptoms (hallucinations and delusions) are strongly related to AD-associated

Psychotic Disorders
Psychotic symptoms (hallucinations and delusions) are strongly related to AD-associated cognitive dysfunction, gradually progressing in parallel with disease severity [182]. In addition, symptoms of personality changes, paranoia, hallucinations, cravings, agitation, and changes in appetite may represent a prodromal noncognitive phenotype of risk for dementia [183].
Antipsychotics are drugs of current use (>50%) to treat BDs in dementia with limited efficacy in aggressive behaviors and psychotic symptoms. These drugs increase mortality and risk of psychomotor disorders and cerebrovascular events. Neuroleptics are prescribed for long periods of time in combination with antidepressants and anti-dementia drugs [186,187].
The dopamine transporter (SLC6A3) gene has been the focus of attention for years in the PGx of antipsychotic drugs. The study of 6 SNPs (rs2652511 (T-844C) and rs2975226 (T-71A) in the 5'-regulatory region, rs2963238 (A1491C) in intron 1, a 30-bp VNTR in intron 8, rs27072 and the 40-bp VNTR in the 3'-region) showed association of allele and genotype frequencies with response to clozapine [188].
An intron-1 SNP (rs6977820) of the DPP6 (dipeptidyl peptidase-like protein-6) gene has been associated with TD in Japanese patients. DPP6 is an auxiliary subunit of Kv4 that regulates the activity of dopaminergic neurons. Decreased expression of DPP6 in the brain can be reversed by haloperidol treatment [197]. Another SNP (rs2445142) in the HSPG2 (heparan sulfate proteoglycan 2) gene has been associated with TD in both Japanese and Caucasian populations [198]. Carriers of the CNR1-rs806374 (T>C) CC genotype are more likely to develop TD and severe motor dysfunction than TT or TC among Caucasians. Cannabinoid receptor 1 (CNR1) activators inhibit movement, and this effect is prevented by rimonabant and selective CNR1 antagonists [199]. A number of SNPs in the SLC18A2 gene that encodes VMAT2 (vesicular monoamine transporter 2) may affect TD, including the rs2015586 marker (with deleterious effects) and the rs363224 marker (with protective effects in carriers of the low-expression AA genotype) [200]. Two VMAT2 inhibitors, Valbenazine and Deutetrabenazine, have been approved for treating TD [201][202][203].
Antipsychotic-induced weight gain occurs in over 30-40% of patients with SCZ. All antipsychotics are associated with weight gain in antipsychotic-naïve and first-episode patients; however, weight gain is greatest in patients treated with the second-generation antipsychotics clozapine and olanzapine. The proportion of patients with body weight gain (>7% baseline) is >20% for ziprasidone, >30% for quetiapine, and 45% for aripiprazole [205]. This ADR is caused by different factors: pharmacological properties of the drug, pharmacogenetic factors, environmental factors, and ethnicity [206]. Hyperprolactinemia is a common ADR in users of neuroleptic drugs. Risperidone-induced prolactin response is associated with 3 UGT1A1 SNPs (UGT1A1*80c.-364C>T, UGT1A1*93 c.-3156G>A, and UGT1A1 c.-2950A>G) [204].
Antipsychotic-induced weight gain occurs in over 30-40% of patients with SCZ. All antipsychotics are associated with weight gain in antipsychotic-naïve and first-episode patients; however, weight gain is greatest in patients treated with the second-generation antipsychotics clozapine and olanzapine. The proportion of patients with body weight gain (>7% baseline) is >20% for ziprasidone, >30% for quetiapine, and 45% for aripiprazole [205]. This ADR is caused by different factors: pharmacological properties of the drug, pharmacogenetic factors, environmental factors, and ethnicity [206]. Hyperprolactinemia is a common ADR in users of neuroleptic drugs. Risperidone-induced prolactin response is associated with 3 UGT1A1 SNPs (UGT1A1*80c.-364C>T, UGT1A1*93 c.-3156G>A, and UGT1A1 c.-2950A>G) [204].
Antipsychotic-induced weight gain occurs in over 30-40% of patients with SCZ. All antipsychotics are associated with weight gain in antipsychotic-naïve and first-episode patients; however, weight gain is greatest in patients treated with the second-generation antipsychotics clozapine and olanzapine. The proportion of patients with body weight gain (>7% baseline) is >20% for ziprasidone, >30% for quetiapine, and 45% for aripiprazole [205]. This ADR is caused by different factors: pharmacological properties of the drug, pharmacogenetic factors, environmental factors, and ethnicity [206].

Mechanism:
Antagonist at multiple neurotransmitter receptors: serotonin 5-HT1A and 5-HT2, dopamine D1 and D2, histamine H1, and adrenergic α1and α2-receptors Effect: Antipsychotic agent; H1-receptor antagonist; Dopaminergic antagonist; Alphaadrenergic antagonist; Serotonergic antagonist; Somnolence; Orthostatic     (minor), CYP2A6, CYP2D6 (major), CYP2J2 (major),        Over 100 permutated pathways may be involved in weight gain regulation in response to neuroleptics, and Genome-wide association studies (GWAS) analysis revealed that Peroxisome proliferator activated receptor gamma (PPARG) and Proprotein convertase, subtilisin/hexin-type 1 (PCSK1) are involved in antipsychotic-induced weight gain [207]. Genetic associations between pathogenic genes and genes involved in lipid metabolism cannot be ruled out as feasible links in body weight changes in response to psychotropic treatments. In fact, lipoprotein lipase (LPL), a key Mechanism: It is a selective antagonist at postsynaptic D 2 and D 3 -receptors. It appears to lack effects on norepinephrine, acetylcholine, serotonin, histamine, or GABA receptors. It also stimulates secretion of prolactin Effect: Antipsychotic agent; Dopaminergic antagonist; Antidepressant effect; Antiemesis. Sedation (>600 mg/day); Dopamine reuptake inhibition (<200 mg/day); Antiemesis, Antimigraine effects; Antivertiginous activity; Prolactin-releasing stimulation Over 100 permutated pathways may be involved in weight gain regulation in response to neuroleptics, and Genome-wide association studies (GWAS) analysis revealed that Peroxisome proliferator activated receptor gamma (PPARG) and Proprotein convertase, subtilisin/hexin-type 1 (PCSK1) are involved in antipsychotic-induced weight gain [207]. Genetic associations between pathogenic genes and genes involved in lipid metabolism cannot be ruled out as feasible links in body weight changes in response to psychotropic treatments. In fact, lipoprotein lipase (LPL), a key enzyme in triglyceride hydrolysis, is expressed in brain regions which are structural substrates of higher activities of the CNS (learning, memory, behavior, cognition), and SNPs in the LPL gene locus (8p22) (rs253 C allele) have been associated with SCZ [208].
Antipsychotic-related ADRs can be substantially reduced with the incorporation of PGx procedures into clinical practice [27,43,103].

Depressive Disorders
Depression is the second most common psychiatric symptom in AD, after apathy. The prevalence of depression in AD varies from 5% to >40% in different studies. Patients with severe AD show a higher prevalence of depression [212,213] and depressive symptoms are associated with a faster rate of memory decline [214]. There is evidence that early life depression can be a risk factor for later life dementia and that later life depression may represent a prodrome to dementia [215], with sex-specific differences [216], especially in cases with cerebral amyloidopathy (>50%) [217]. Furthermore, depressed patients with mild cognitive impairment (MCI) have worse cognitive performance and greater loss of gray-matter volume in the cerebellum and parahippocampal gyrus [218]. Low psychomotor speed has also been associated with an increased risk of developing dementia and depressive symptoms [219]. Cardiovascular risk factors may contribute to depression in patients with MCI [220]. Late-life depression (LLD) affects 15% of the elderly population. CYP2D6, SLC6A4 5-HTTLPR, and brain-derived neurotrophic factor (BDNF) variants influence the PGx of this condition, as recently reported by the Clinical Pharmacogenetics Implementation Consortium [221].
Some studies indicate that the APOE genotype may influence the incidence of BDs and treatment in dementia [111,117], while others did not find association of APOE-4 with depression, anxiety, apathy, agitation, irritability, or sleep disturbances in cognitively impaired subjects [222]. Genome-wide association studies (GWAS) identified 31 genes located in 19 risk loci for major depressive disorder (MDD). Common and rare variants of L3MBTL2 are associated with AD. mRNA expression levels of SORCS3 and OAT are differentially expressed in AD brain tissues, and 13 MDD risk genes may interact with core AD genes such as HACE1, NEGR1, and SLC6A15 [223].
The treatment of depression in dementia can be pharmacological, with antidepressants, especially selective serotonin reuptake inhibitors as a first choice, or nonpharmacological (emotion-oriented therapies, behavioral, and cognitive-behavioral modification programs; structured activity programs; sensory-stimulation therapies; multisensory approaches; music therapy; and mindfulness-based interventions) [224]. Meta-analyses of double-blind randomized controlled trials comparing antidepressants versus placebo for depression in AD revealed inefficacy in most cases with different drugs (sertraline, mirtazapine, imipramine, fluoxetine, and clomipramine) [225].
The mechanisms underlying depression in dementia still remain unclarified [226]. About 60% of depressive patients receive an inappropriate medication according to their pharmacogenetic background [66,227,228], and community psychiatrists and pharmacists are more accurate in their psychotropic prescriptions when they know the CYP profile of their patients [228][229][230].
CYP2C19 and CYP2D6 variants affect the occurrence of ADRs in patients treated with selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, sertraline, fluvoxamine, fluoxetine, and paroxetine), including anxiety, nightmares, and panic attacks associated with CYP2D6 and electrocardiogram (ECG)-prolonged QT associated with CYP2C19 [231]. Prolonged QTc interval is prevalent in patients with moderate-severe dementia, with behavioral symptoms, with global and temporal atrophy, and with leukoaraiosis [232]. A pharmacogenetic risk score has been proposed with top-scoring SNPs (rs12248560, rs878567, and rs17710780). The HTR1A rs878567 and CYP2C19 rs12248560 variants showed association with depression severity [233]. ACE variants influence mood in AD [111]. The coadministration of ACE inhibitors and statins with antidepressants may affect therapeutic outcomes [234]. Table 4. Pharmacological profile and pharmacogenetics of selected antidepressants.

Mechanism:
Increases synaptic concentration of serotonin and/or norepinephrine in CNS by inhibition of their reuptake by presynaptic neuronal

Mechanism:
Selectively inhibits serotonin reuptake in the presynaptic neurons and has minimal effects on norepinephrine or dopamine Effect: Serotonin uptake inhibition;

Category: Norepinephrine inhibitor
Mechanism: It is a highly selective and potent inhibitor of noradrenaline reuptake. Only has weak effect on 5-HT reuptake Effect: Adrenergic uptake inhibitor; Antidepressant activity; Anti-anxiety activity; Attention enhancer CYP2C19 and CYP2D6 variants affect the occurrence of ADRs in patients treated with selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, sertraline, fluvoxamine, fluoxetine, and paroxetine), including anxiety, nightmares, and panic attacks associated with CYP2D6 and electrocardiogram (ECG)-prolonged QT associated with CYP2C19 [231]. Prolonged QTc interval is prevalent in patients with moderate-severe dementia, with behavioral symptoms, with global and temporal atrophy, and with leukoaraiosis [232]. A pharmacogenetic risk score has been proposed with top-scoring SNPs (rs12248560, rs878567, and rs17710780). The HTR1A rs878567 and CYP2C19 rs12248560 variants showed association with depression severity [233]. ACE variants influence mood in AD [111]. The coadministration of ACE inhibitors and statins with antidepressants may affect therapeutic outcomes [234].
The influence of PGx factors on the pharmacogenetics and pharmacodynamics of many antidepressants has been reasonably well documented [55,66,[235][236][237]; however, important aspects such as body weight gain, suicidality, cyclothymic reactions, cardiovascular risks, and potential neurotoxicity still remain obscure [55].
Lithium is the gold standard for the treatment of bipolar disorder (BPD) and BPD-like symptoms in a reduced number of cases with dementia. The response to lithium is very variable and depends on the PGx background of each patient [238]. Lithium PGx is very complex. Caution and personalized dose adjustment is highly recommended in patients with the following genotypes: BCR (Asn796Ser), BDNF (C/G (rs988748) and G/A (Val66Met)), CACNG2 (rs2284017, rs2284018, and rs5750285), GSK3B The influence of PGx factors on the pharmacogenetics and pharmacodynamics of many antidepressants has been reasonably well documented [55,66,[235][236][237]; however, important aspects such as body weight gain, suicidality, cyclothymic reactions, cardiovascular risks, and potential neurotoxicity still remain obscure [55].

Anxiety Disorders
Anxiety-like disorders are present in 30-40% of cases with dementia during the disease process. Anxiety is a risk factor for dementia [239,240], and anxiety-like behaviors are persistent in patients with dementia. Early-onset AD patients exhibit greater prevalence of all BDs, especially anxiety, irritability, and sleep disorders [241].
The neurobiology of anxiety in dementia is unknown. Subjective cognitive decline (SCD) (self-reported cognitive deficits), without measurable cognitive impairment, has been associated with brain structural alterations and APOE-4. SCD cases show decreased total cortical volumes and cortical surface area, which are especially prominent in APOE-4 carriers. Anxiety symptoms are negatively associated with the right cortical surface area in APOE-4 noncarriers with SCD [242]. Depression, anxiety, and cerebrovascular risk contribute to SCD [243].
Benzodiazepines are currently prescribed for ameliorating this symptomatology; however, benzodiazepines contribute to cognitive and psychomotor dysfunction [244].

Sleep Disorders
Chronic sleep disorders might represent a risk factor for dementia, and alterations in circadian rhythms and consequent sleep disorders are common in AD and age-related disorders [245][246][247][248]. The neurobiology of circadian rhythms in AD is not well documented. Different neurotransmitters influence circadian changes and sleep disorders (insomnia, parasomnias, circadian rhythm sleep-wake disorders, hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders), including melatonin, histamine, GABA, hypocretin, dopamine, noradrenaline, serotonin, and adenosine. Genomic alterations in these systems (e.g., pathogenic genes) may affect the efficacy and safety of anxiolytics and hypnotics used in the treatment of some of these disorders [55].
Over 100 genes have been associated with sleep disorders in AD [249]. In the triple transgenic AD mouse model (3× Tg-AD), there is an abnormal expression of Per genes in the suprachiasmatic nucleus (SCN) [250]. The glymphatic system might be an effective mechanism of brain Aβ-amyloid clearance particularly effective during sleep. Aquaporin-4 may play a role in glymphatic function, since ablation of Aquaporin-4 results in impairment of Aβ clearance mechanism and increased brain Aβ-amyloid deposition. The AQP4 variant rs72878776 is associated with poorer overall sleep quality, and other SNPs might moderate the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, and rs151246) and duration (rs72878776, rs491148, and rs2339214) on brain Aβ-amyloid burden [251]. Homer1a and mGluR1/5 are implicated in sleep function to weaken synapses during sleep and to restore synapse homeostasis [252].
Evening secretion of melatonin is delayed and mildly impaired in patients with AD [253]. Rapid eye movement (REM) sleep influences memory consolidation. Noradrenaline participates in the regulation of REM sleep to maintain neuronal integrity and brain house-keeping functions [254].
Sleep dysfunction and Aβ deposition show synergistic effects to impair brain function. Brain Aβ deposition is associated with subjective measures of sleep quality and cognition. Nocturnal awakenings are associated with Aβ deposition in the precuneus and poor cognitive performance [255]. Extracellular levels of Aβ and tau show a fluctuating pattern during the normal sleep-wake cycle. Increased wakefulness and disturbed sleep lead to increased Aβ production and decreased Aβ clearance; additionally, chronic wakefulness increases Aβ aggregation and deposition, and Aβ accumulation results in disturbed sleep. Sleep deprivation increases brain and CSF tau levels and the spread of tau protein aggregates in neural tissues, correlating with decreased nonrapid eye movement (NREM) sleep slow wave activity [256,257].
Sleep disorders may precede cognitive impairment. Sleep disturbances alter periodic sleep architecture and electroencephalogram (EEG) patterns in prodromal stages [258]. Age-related cognitive impairment is associated with reduced delta, theta, and sigma power as well as spindle maximal amplitude during NREM sleep. Early sleep biomarkers of potential cognitive decline are poor sleep consolidation, lower amplitude, and faster frequency of spindles [259]. Decreased nonrapid eye movement (NREM) sleep slow wave activity associates with Aβ deposition and tauopathy. Aβ decreases nonrapid eye movement sleep and increases wakefulness. Aβ upregulates the expression levels of tau, pTau, orexin A, and adenosine A1 receptor [260]. Orexin receptor antagonists (e.g., Suvorexant) have been proposed as potential candidates for the treatment of sleep disorders and BDs in AD [261].

Barbiturates Drug Properties Pharmacogenetics
Sleep disorders may precede cognitive impairment. Sleep disturbances alter periodic sleep architecture and electroencephalogram (EEG) patterns in prodromal stages [258]. Age-related cognitive impairment is associated with reduced delta, theta, and sigma power as well as spindle maximal amplitude during NREM sleep. Early sleep biomarkers of potential cognitive decline are poor sleep consolidation, lower amplitude, and faster frequency of spindles [259]. Decreased nonrapid eye movement (NREM) sleep slow wave activity associates with Aβ deposition and tauopathy. Aβ decreases nonrapid eye movement sleep and increases wakefulness. Aβ upregulates the expression levels of tau, pTau, orexin A, and adenosine A1 receptor [260]. Orexin receptor antagonists (e.g., Suvorexant) have been proposed as potential candidates for the treatment of sleep disorders and BDs in AD [261].

Mechanism:
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the CNS, including the limbic system, reticular formation. Enhancement of inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions

Epilepsy
Epilepsy is a prevalent disorder in dementia with prevalence and incidence rates 2-6-fold higher than in age-matched healthy subjects. Subclinical epileptiform activity can lead to accelerated cognitive decline. Aβ deposition may influence the propagation of synchronized abnormal discharges via excitatory pathways [262].
There is a complex epileptogenesis-associated dysregulation of proteins involved in amyloid β processing and regulation in the hippocampus (HC) and parahippocampal cortex during epileptogenesis, in which there is also involvement of tau and proteins of the mitochondrial complexes I, III, IV, and V [263]. Seizures are more prevalent in early-onset AD with rapid progression [264], correlating with high CSF total tau protein levels [265]. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), which is an α-secretase in APP processing, has been associated with epilepsy as a stage-dependent modulator of epileptogenesis [266].
Potential pathogenic genes for epilepsy include ion channel genes (e.g., SCN1A, KCNQ2, SCN2A, and SCN8A), which account for nearly half of epilepsy genes, together with a number of additional genes, such as CDKL5, STXBP1, PCDH19, PRRT2, LGI1, ALDH7A1, MECP2, EPM2A, ARX, and SLC2A1 [267]. There is also an association of MTHFR rs1801133 and ABCC2 rs717620 with susceptibility to generalized tonic-clonic epilepsy, while ABCB1 rs717620 is associated with poor response to antiepileptics [268]. The influence of some of these genes in PGx has been investigated under different therapeutic paradigms [55].

Epilepsy
Epilepsy is a prevalent disorder in dementia with prevalence and incidence rates 2-6-fold higher than in age-matched healthy subjects. Subclinical epileptiform activity can lead to accelerated cognitive decline. Aβ deposition may influence the propagation of synchronized abnormal discharges via excitatory pathways [262].
There is a complex epileptogenesis-associated dysregulation of proteins involved in amyloid β processing and regulation in the hippocampus (HC) and parahippocampal cortex during epileptogenesis, in which there is also involvement of tau and proteins of the mitochondrial complexes I, III, IV, and V [263]. Seizures are more prevalent in early-onset AD with rapid progression [264], correlating with high CSF total tau protein levels [265]. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), which is an α-secretase in APP processing, has been associated with epilepsy as a stage-dependent modulator of epileptogenesis [266].
Potential pathogenic genes for epilepsy include ion channel genes (e.g., SCN1A, KCNQ2, SCN2A, and SCN8A), which account for nearly half of epilepsy genes, together with a number of additional genes, such as CDKL5, STXBP1, PCDH19, PRRT2, LGI1, ALDH7A1, MECP2, EPM2A, ARX, and SLC2A1 [267]. There is also an association of MTHFR rs1801133 and ABCC2 rs717620 with susceptibility to generalized tonic-clonic epilepsy, while ABCB1 rs717620 is associated with poor response to antiepileptics [268]. The influence of some of these genes in PGx has been investigated under different therapeutic paradigms [55].
Treatment of seizures in AD with low-dose antiepileptic drugs (AEDs) is usually well tolerated and efficacious, and selected AEDs might also help in slowing-down disease progression [269,270]. Anticonvulsants may suppress seizures in up to two-thirds of all patients, with no apparent effects on long-term prognosis [271].
UGT2B7 G211T and C161T polymorphisms affect the pharmacokinetics and pharmacodynamics of valproic acid (VPA) [276]. Carriers of the variant UGT1A6 19T>G, 541A>G, and 552A>C allele require higher VPA dosages than noncarriers, and carriers of the variant GRIN2B -200T>G allele are more likely to require lower VPA dosages than noncarriers [277]. VPA-related liver damage has been associated with the formation of a hepatotoxic 4-ene metabolite mediated by CYP2C9 and CYP2A6 enzymes [278]. ABAT rs1731017, SCN2A rs2304016, and ALDH5A1 rs1054899 are associated with VPA response in Chinese patients [279]. Female CYP2C19-PMs are more susceptible to VPA-induced weight gain in the Japanese population [280], and SNPs in the leptin receptor (LEPR) (rs1137101) and ankyrin repeat kinase domain containing 1 (ANKK1) (rs1800497) show associations with VPA-induced weight gain in the Chinese population [281]. Oral clearance (CL/F) of VPA in patients with the LEPR-A668G and G668G (rs1137101) variants is lower than in patients with the LEPR-A668A genotype [282]. Meropenem decreases VPA plasma levels when coadministered together. This interaction is triggered by inhibition of acylpeptide hydrolase (APEH) activity with meropenem. The study of VPA-d6 β-D-glucuronide (VPA-G) concentration in APEH rs3816877 and rs1131095 carriers revealed that patients with the APEH rs3816877 C/C genotype show higher levels than C/T carriers in the Chinese population [283]. Valproate-related neuroprotection in experimentally triggered epileptic seizures has been associated with PKC-dependent GABAAR γ2 phosphorylation at serine 327 residue [284]. SOD2 Val16Ala polymorphism may affect γ-glutamyltransferase (GGT) elevation in epileptic patients treated with VPA [285].
CACNA1G, CACNA1H, CACNA1I, and ABCB1 variants are associated with differential short-term seizure outcome in childhood absence epilepsy. In patients treated with ethosuximide, CACNA1H rs61734410/P640L and CACNA1I rs3747178 are more prevalent among not-seizure-free patients, and in patients treated with lamotrigine, ABCB1 rs2032582/S893A is more frequent in not-seizure-free patients, whereas CACNA1H rs2753326 and rs2753325 are more common in seizure-free patients [305].
Resistant epilepsy is an important problem in over 20% of patients treated with antiepileptics [306]. Pharmaco-resistance is directly linked to dysfunctions in the pharmacoepigenetic machinery [61]. The C3435T variant of the ABCB1 gene has been proposed as a crucial factor for drug resistance in epilepsy. ABCB1-C3435C carriers show a risk of pharmacoresistance in some studies, but this association has been questioned after further analyses [307]. The ABCB1 G2677T T (rs1128503) and C3435T T (rs1045642) alleles and the TT, CTT, and TTT haplotypes are associated with drug-resistant epilepsy in specific populations [308]. ABCC2 rs717620 -24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes are overrepresented in epileptic patients resistant to antiepileptic drugs in the Chinese population, whereas ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not found to be associated with drug-resistant epilepsy in this population. The frequency of the haplotype TGT (ABCC2 -24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients is double that of responsive patients [309]. The TAGAA haplotype in CACNA1A accumulates in drug-resistant patients in the Chinese population [310]. Glucose type-1 transporter (GLUT1) deficiency syndrome, caused by mutations in the SLC2A1 gene, exhibits pharmacoresistance to antiepileptics. Screening of SLC2A1 pathogenic variants can predict drug response and optimization of antiepileptic drugs for the treatment of this health condition [311]. The SCN1A IVS5-91G>A AA and ABCC2 c.1249G>A GA genotypes have been shown to be associated with carbamazepine/oxcarbamazepine-resistant epilepsy in the Chinese Han population. The frequency of SCN1A-AA and ABCC2-AC haplotypes is higher in drug-resistant patients than in responsive patients [312]. Association of ABCC2 rs2273697 and rs3740066 polymorphisms and drug-resistant epilepsy has been reported in Asia Pacific epilepsy cohorts [313]. PCDH19 mutations may cause pharmacoresistant epilepsy and intellectual disability in Dravet-like syndromes. A retrospective study of antiepileptic therapy in females with PCDH19 mutations showed that the most effective drugs in these cases are clobazam and bromide, with responder rates of 68% and 67%, respectively [314]. Clobazam binds to stereospecific receptors on the postsynaptic GABA neuron at several sites within the CNS (limbic system and reticular formation) and enhances the inhibitory effect of GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions, which results in hyperpolarization and stabilization. Clobazam is extensively metabolized by CYP enzymes. Its major metabolite is N-desmethylclobazam (norclobazam), which also display antiepileptic activity. Clobazam is a major substrate of CYP2C19 and CYP3A4 and a minor substrate of CYP2B6 and CYP2C18. CYP2C19-PMs show higher plasma levels of clobazam and increased risk of ADRs. Caution and personalized dose adjustment is recommended in patients with the following genotypes: CYP2C19 (CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*6, CYP2C19*7, CYP2C19*8, CYP2C19*17), CYP3A4 (CYP3A4*1, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*15, CYP3A4*17, CYP3A4*18, CYP3A4*19), and CYP3A5 (CYP3A5*3) [55,56] (Table 6).
In Japanese patients with Dravet syndrome, it seems that CYP2C19 variants may influence a positive response to the antiepileptic effects of stiripentol [315]. Genotype combinations of GABRA1 rs6883877, GABRA2 rs511310, and GABRA3 rs4828696 may affect responses to antiepileptic drugs [316]. G-aminobutyric-acid (GABA) is the principal inhibitory neurotransmitter in the CNS. Imbalances in GABAergic neurotransmission are involved in the pathophysiology of epilepsy and AD. GABA transporters (GATs) regulate the influx-efflux of GABA with sodium and chloride at the synaptic cleft. GATs belong to the solute carrier 6 (SLC6) transporter family: GAT1-3 (SLC6A1, SLC6A13, and SLC6A11) and betaine/GABA transporter 1 (BGT1 and SLC6A12). BGT1 is a potential target for the treatment of epilepsy. The GAT1/BGT1 selective inhibitor EF1502 and the BGT1 selective inhibitor RPC-425 display anticonvulsant effects [317].  (Table 6).
In Japanese patients with Dravet syndrome, it seems that CYP2C19 variants may influence a positive response to the antiepileptic effects of stiripentol [315]. Genotype combinations of GABRA1 rs6883877, GABRA2 rs511310, and GABRA3 rs4828696 may affect responses to antiepileptic drugs [316]. -aminobutyric-acid (GABA) is the principal inhibitory neurotransmitter in the CNS. Imbalances in GABAergic neurotransmission are involved in the pathophysiology of epilepsy and AD. GABA transporters (GATs) regulate the influx-efflux of GABA with sodium and chloride at the synaptic cleft. GATs belong to the solute carrier 6 (SLC6) transporter family: GAT1-3 (SLC6A1, SLC6A13, and SLC6A11) and betaine/GABA transporter 1 (BGT1 and SLC6A12). BGT1 is a potential target for the treatment of epilepsy. The GAT1/BGT1 selective inhibitor EF1502 and the BGT1 selective inhibitor RPC-425 display anticonvulsant effects [317]. transmission-inhibitory actions. May depress activity in the nucleus ventralis of the thalamus or decrease synaptic transmission or decrease summation of temporal stimulation leading to neural discharge by limiting influx of sodium ions across cell membrane or other unknown mechanism. May decrease the turnover of γaminobutyric acid (GABA). Stimulates the release of ADH and potentiates its action in promoting reabsorption of water. Chemically related to tricyclic antidepressants.

Mechanism:
Exact mechanism of anticonvulsant, sedative, and antipanic effects is unknown; however, mechanism appears to be related to the drug's ability to enhance the activity of γ-aminobutyric acid (GABA). Suppresses the spike-and-wave discharge in absence seizures by depressing nerve transmission in the motor cortex. Depresses all levels of the CNS, including the limbic and Mechanism: Exact mechanism of anticonvulsant, sedative, and antipanic effects is unknown; however, mechanism appears to be related to the drug's ability to enhance the activity of γ-aminobutyric acid (GABA). Suppresses the spike-and-wave discharge in absence seizures by depressing nerve transmission in the motor cortex. Depresses all levels of the CNS, including the limbic and reticular formation, by binding to the benzodiazepine site on the GABA receptor complex and modulating GABA Effect: Anxiolytics, Sedatives, and Hypnotics; Benzodiazepines. Anticonvulsants; Benzodiazepines
Exact mechanism of anticonvulsant action unknown. Increases seizure threshold in cortex and basal ganglia and reduces synaptic response to lowfrequency repetitive stimulation. Suppresses paroxysmal spike and wave activity of the EEG associated with lapses of consciousness common in absence seizures
Exact mechanism of anticonvulsant action unknown. Increases seizure threshold in cortex and basal ganglia and reduces synaptic response to lowfrequency repetitive stimulation. Suppresses paroxysmal spike and wave activity of the EEG associated with lapses of consciousness common in absence seizures
Exact mechanism of anticonvulsant action unknown. Increases seizure threshold in cortex and basal ganglia and reduces synaptic response to lowfrequency repetitive stimulation. Suppresses paroxysmal spike and wave activity of the EEG associated with lapses of consciousness common in absence seizures Mechanism: Felbamate, a dicarbamate, is an anticonvulsant agent. Exact mechanism of action unknown, but it is suggested that it increases seizure threshold and reduces seizure spread. In vitro studies indicate that felbamate has weak inhibitory effects on binding at GABA receptors and benzodiazepine receptors. The monocarbamate, p-hydroxy, and 2-hydroxy metabolites of felbamate appear to contribute little, if any, to the anticonvulsant action of the drug Effect: Anticonvulsants Table 6. Cont.

Antiepileptics Drug
Properties Pharmacogenetics  Barbiturates depress sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, barbiturates exhibit anticonvulsant activity. They also produce dose-dependent respiratory depression

Antiepileptics Drug
Properties Pharmacogenetics gamma-aminobutyric acid (GABA). It is thought that binding to GABA uptake carrier inhibits uptake of GABA into presynaptic neurons, allowing availability of increased amount of GABA to postsynaptic neurons. Based on in vitro studies, tiagabine does not inhibit uptake of dopamine, norepinephrine, serotonin, glutamate, or choline

Conclusions
Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6-10 drugs/day with the consequent risk for drug-drug interactions (DDIs) and adverse drug reactions (ADRs > 80%) which accelerate cognitive decline. PGx intervention may prevent ADRs and DDIs. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms (DNA methylation, chromatin remodeling/histone changes, and miRNAs). CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. In multifactorial treatments, APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-EMs are the best responders and CYP2D6-PMs are the worst responders. ACHE-BCHE variants also affect the pharmacogenetic outcome as well as some genes encoding components of the epigenetic machinery.
Antipsychotics show limited efficacy in aggressive behaviors and psychotic symptoms and may increase mortality and risk of psychomotor disorders and cerebrovascular events. Major ADRs with antipsychotics are extrapyramidal symptoms, tardive dyskinesia, weight gain, hyperprolactinemia, and agranulocytosis. Antipsychotics are associated with the activity of ≈100 pharmagenes; antidepressants are associated with 600; and anxiolytics, hypnotics, and sedatives are associated with 445. CYP enzymes are involved in 100% of drugs approved for the treatment of depression, and about 60% of depressive patients are receiving an inappropriate medication according to their pharmacogenetic background. Carbamazepine, oxcarbazepine, or phenytoin may cause delayed-hypersensitivity reactions associated with the HLA antigen allele HLA-B*15:02.
The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

Further Considerations
Drug efficacy and safety are fundamental issues in dementia due to the complexity of the disorder and comorbidities which require polypharmacy [43]. Over 50% of patients over 60 years of age suffering chronic CNS disorders currently take 6-12 drugs/day with a high risk of drug toxicity, ADRs, and DDIs [43,56]. Over 20% of patients with depression develop dementia in a period of approximately 10 years. The chronic use of anticholinergic antidepressants might contribute to this pathogenic transformation [318]. It is also well-known that over 60% of patients chronically treated with antipsychotics develop extrapyramidal symptoms which may induce severe motor disability [319]. Over 80% of nursing home residents are daily consumers of psychotropic drugs [320,321] which are prescribed in excessive doses, for excessive duration, and without adequate monitoring and/or indications for their use [322]. Prescribing errors (≈50%) are common in patients treated with anti-dementia drugs [42], and potentially inappropriate prescribing (PIP) occurs in almost 80% of patients with dementia [323].
With appropriate PGx intervention, the frequency and intensity of PIP and ADRs may be reduced in approximately 50% of the cases. AD patients show diverse age-related comorbidities which require polypharmacy. The implementation of PGx procedures may help to minimize drug-drug interactions. For instance, CYP2C19 variants influence the effects of proton-pump inhibitors and the onset of infections [324]. ACE variants affect the pharmacokinetics and pharmacodynamics of ACE inhibitors which may interact with psychotropic drugs, contributing to cerebrovascular dysfunction [229]. Another important issue is the use of anticoagulants in patients with dementia [103]. Different antithrombotic drugs (Acenocoumarol, Acetylsalicylic acid, Argatroban, Bivalirudin, Cilostazol, Clopidogrel, Dabigatran, Rivaroxaban, Dipyridamole, Lepirudin, Prasugel, Ticagrelor, Ticlopidine, and Warfarin) can be used in patients with atrial fibrillation, thrombophlebitis, and thromboembolic or ischemic stroke. Warfarin is one of the most common anticoagulants due to its low cost; however, its narrow therapeutic window makes it a candidate to a few ADRs in patients with dementia. Warfarin prolongs prothrombin time (PT) and activated partial thromboplastin time (APTT), and phytonadione (vitamin K1) reverses its anticoagulant effect. Warfarin is a substrate of CALU, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP3A4/5, CYP4F2, EPHX1, and GGCX; an inhibitor of CYP2C9, CYP2C19, and VKORC1; and an inducer of CYP2C9; and is transported by ABCB1. CYP2C9 and VKORC1 variants are determinant in warfarin efficacy and safety [55]. VKORC1 variants and CYP2C9*3 are clearly associated with warfarin maintenance dosages. CYP2C9 and VKORC1 genotypes help to identify normal responders (60%), sensitive responders (35%), and highly sensitive responders (3%) to warfarin and characterized patients who can benefit from edoxaban compared with warfarin [325]. VKORC1-AG and GG carriers need higher doses than patients with AA genotypes, and CYP2C9*1/*3 carriers need doses lower than patients with the CYP2C9*1/*1 wild genotype [326]. In the Chinese region of Xinjiang, patients with atrial fibrillation carrying the CT and TT genotypes in the GGCX gene rs259251 loci need higher warfarin doses than GGCX-CC carriers [327].
ADRB1 Ser49Gly and Arg389Gly variants are associated with cardiovascular and β-blocker response outcomes. In patients with previous history of stroke, the ADRB1 Gly49 polymorphism is associated with cardiovascular and cerebrovascular ADRs among β-blocker users [328].
In patients with minor ischemic stroke, platelet receptor gene (P2Y12 and P2Y1) and glycoprotein gene (GPIIIa) polymorphisms influence antiplatelet drug responsiveness and clinical outcomes [329], and there are genetic differences (rs12143842) in the response of stroke patients to antihypertensive drugs (chlorthalidone, amlodipine, or lisinopril), especially regarding HNRNPA1P4 and NOS1AP variants in African Americans and PRICKLE1 and NINJ2 variants in non-Hispanic Whites [330].
The platelet-aggregation inhibitor Clopidogrel may also cause frequent complications. This antithrombotic agent is a substrate of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5; and an inhibitor of CYP2B6, CYP2C9, and CYP2C19; and is transported by ABCB1. CYP2C19*2 (G681A and rs4244285), CYP2C19*3 (G363A and rs4986893), CYP2C19*17 (C806T and rs12248560), and ABCB1 (C3435T and rs1045642) carriers with ischemic stroke are particularly sensitive to clopidogrel ADRs [55]. Clopidogrel resistance is frequent in patients with chronic kidney disease. Kidney dysfunction alters the association between CYP2C19 variants and clopidogrel effects in patients with stroke or transient ischemic attack. Carriers of CYP2C19 loss-of-function alleles (CYP2C19*2 and *3) have higher odds of new stroke than noncarriers [332,333] and increased risk of thromboembolic complications following neurointerventional procedures [334]. The AKR1D1*36 (rs1872930) allele is associated with the risk of major adverse cardiovascular and cerebrovascular events in clopidogrel-treated patients [335]. About 16-50% of patients treated with clopidogrel show platelet reactivity and an increased risk of ischemic events. Some methylated CpG sites have been associated with increased stroke recurrence. Lower cg03548645 (TRAF3) DNA methylation correlates with increased platelet aggregation in patients with stroke [336].
Studies on the PGx of anticoagulants for stroke prevention in patients with atrial fibrillation are not conclusive and deserve further investigation to optimize this currently used pharmacological intervention with still unclear results [337].
Orthopedic surgery is relatively frequent in patients with NDDs who experience perioperative neurocognitive disorders (delirium and postoperative cognitive dysfunction) which increase mortality [338]. PGx assessment is highly recommended for selection of appropriate anesthetics and postsurgical treatments in order to reduce postoperatory BDs and accelerated cognitive deterioration [55].
Opioid use disorder (OUD) is infrequent in AD; however, in AD cases treated with opioids, it is important to take into account that patients with at least one copy of the CYP3A4*1B allele exhibit an accelerated rate of metabolism compared to the wild-type allele CYP3A4*1 [339] and that CYP2D6-UMs show a better response to opiates than EMs, IMs, and PMs [55].
Several essential elements and metals (zinc, aluminum, copper, and cadmium), environmental toxicants, air pollutants (e.g., nanoparticles, particulate matter, ozone, and traffic-related air pollution), inappropriate medications, and drugs of abuse (amphetamines, cannabis, cocaine, and heroin) may contribute to neurotoxicity and may interfere with conventional treatments in dementia. Over 30% of patients with prodromal dementia are current users of anticholinergic drugs [340]. Chronic exposure to these products alters behavior and deteriorates cognition and psychomotor function in a dose-dependent fashion [341][342][343]. The pharmacogenetic genotyping of detoxification systems may help to predict risks in susceptible subjects [55].
It is also most important to elucidate the mechanisms underlying the drug-resistance phenomenon, which occurs in over 40% of cases with NPDs and in over 70% of cases with neoplastic processes [61,71]. Globally, over 20% of patients are resistant to conventional drugs [344,345] and it is estimated that pharmacogenetic and pharmacoepigenetic factors are important contributors to drug resistance [61,[346][347][348].
Important issues to take into account in the coming years for the appropriate management of dementia are the identification of presymptomatic biomarkers and the discovery of effective drugs. Predictive markers associated with pathogenic genes for the presymptomatic diagnosis of dementia should incorporate both genomic and epigenetic signatures. Concerning the development of novel anti-pathogenic drugs, actual facts show that most CNS drugs are repressive rather than neuroprotective based on the regulation of a restrictive number of neurotransmitters; however, brain function depends upon the interplay of thousands of neuronal-glial factors pending full characterization. The discovery of novel anti-pathogenic drugs with neuroprotective properties is urgently needed to efficiently treat the different forms of brain dysfunction in dementia. The development of new drugs and clinically validated methods of identifying patients for a specific treatment should rely on PGx strategies.
Funding: This paper was funded by IABRA (International Agency for Brain Research and Aging), Corunna, Spain.