Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Abstract

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.

Schizophrenia; Recent Cognitive and Treatment Approaches Using Induced Pluripotent Stem Cells

“…46 By taking advantage of recent studies and approaches, by exploring biological pathways and analyzing genes related to schizophrenia, numerous related genes have identified which listed in Table 1. 45,47 Biological mechanisms involving synaptic transmission, regulation of membrane potential, and transmembrane ion transport have identified as before cellular applications related to schizophrenia genes. 48 Additionally, some genetically neurological disorders that their induced pluripotent stem cells (iPSCs) associate with schizophrenia patients.…”

Influence of Pathogenic and Metabolic Genes on the Pharmacogenetics of Mood Disorders in Alzheimer’s Disease

“…Alzheimer’s disease (AD) is the most frequent form of dementia (>50%), followed by vascular (VD) and mixed dementia (MXD) (30–40%) and other phenotypic presentations of neurocognitive disorders (NCDs) [ 1 ]. In patients over 70–75 years of age, MXD is the most prevalent form of dementia (>70%) [ 2 ].…”

“…Furthermore, some neuropsychiatric disorders may increase the risk for late-onset dementia, and dementia may increase the risk for delayed-onset BDs [ 17 ]. Over 50% of AD patients have comorbidities, and the presence of gene variants, together with metabolic disorders, cerebrovascular risk, premorbid personality, and inappropriate management may contribute to BDs in AD [ 2 ]. Although there is no prototypical pattern of BDs in different types of dementia, anxiety, depression, apathy, dysphoria, agitation, aggression, delusions, and hallucinations are frequent distressing symptoms in dementia that require pharmacological intervention [ 2 , 13 ].…”

“…The pharmacogenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes under the promiscuous regulation of epigenetic factors such as DNA methylation, chromatin/histone changes, and miRNAs [ 32 , 33 ]. In AD, most pharmacogenetic studies used apolipoprotein E (APOE) and cytochrome P450 (CYP) variants, as a reference, since the presence of the APOE-4 allele is a major pathogenic risk factor for dementia and most acetylcholinesterase inhibitors are metabolized via CYP enzymes, with the exception of rivastigmine [ 2 , 4 , 6 , 18 , 34 , 35 ]. In general, APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders to treatments either in monotherapy or in combination regimes [ 2 , 4 , 6 , 18 , 34 , 35 ].…”

“…In AD, most pharmacogenetic studies used apolipoprotein E (APOE) and cytochrome P450 (CYP) variants, as a reference, since the presence of the APOE-4 allele is a major pathogenic risk factor for dementia and most acetylcholinesterase inhibitors are metabolized via CYP enzymes, with the exception of rivastigmine [ 2 , 4 , 6 , 18 , 34 , 35 ]. In general, APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders to treatments either in monotherapy or in combination regimes [ 2 , 4 , 6 , 18 , 34 , 35 ]. Among the CYP variants, CYP2D6 normal metabolizers (NM) tend to be the best responders to treatment, CYP2D6 intermediate metabolizers (IM) show an intermediate response, and CYP2D6 poor metabolizers (PM) and ultra-rapid metabolizers (UM) tend to behave as the worst responders to conventional anti-AD treatments [ 2 , 4 , 6 , 18 , 34 , 35 , 36 , 37 ].…”