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.
Highlights
Alzheimer’s disease (AD) is the most prevalent form of dementia (>50%), followed by vascular (VD), mixed dementia (MXD) (30–40%), and other modalities of neurodegenerative disorders (NDDs) (Lewy body dementia (LBD), frontotemporal dementia (FTD), prion dementia, Pick’s dementia, Parkinson–dementia complex (PDC); and comorbid FTD-amyotrophic lateral sclerosis) (5–10%)
Genomic defects (Table 1), epigenetic aberrations, cerebrovascular dysfunction, and multiple environmental factors are the major risk factors that precipitate pathogenic cascades leading to the clinical phenotype of dementia which is characterized by progressive cognitive deterioration, behavioral changes, functional decline, and classical neuropathological hallmarks [1,2,3,4,5,6]
According to data available in the World Guide for Drug Use and Pharmacogenomics [55] and the EuroPharmaGenics (EPG) database [56] concerning central nervous system (CNS) drugs (Figure 1), the best-known genes of the pharmacogenetic machinery involved in the processing of antiepileptic, antidepressant, anxiolytic, hypnotic, sedative, antiparkinsonian, and antipsychotic drugs are mechanistic and metabolic genes, and poorly investigated genes are those involved in pathogenic mechanisms, transporters, and pleiotropic genes (Figure 1)
Summary
Alzheimer’s disease (AD) is the most prevalent form of dementia (>50%), followed by vascular (VD), mixed dementia (MXD) (30–40%), and other modalities of neurodegenerative disorders (NDDs) (Lewy body dementia (LBD), frontotemporal dementia (FTD), prion dementia, Pick’s dementia, Parkinson–dementia complex (PDC); and comorbid FTD-amyotrophic lateral sclerosis) (5–10%). Over 50% of AD patients show comorbidities (TDP-43 and Lewy bodies) which associate with frontotemporal lobar degeneration and LBD Some of these comorbidities might explain BDs in dementia. Current ADRs in the elderly population are associated with benzodiazepines, neuroleptics, antidepressants, and antihypertensives These drugs may cause falls; delirium and excess mortality increase with polypharmacy; over-infections are frequent in patients with inappropriate use of broad-spectrum antibiotics; increased risk of stroke is observed in patients with dementia treated with antipsychotics; nonsteroidal anti-inflammatory drugs may cause hypertensive crises, bleeding, and cerebrovascular problems; and other ADRs have been extensively reported worldwide [43,44,45,46]. The present review explores available information for personalized treatment of dementia in the areas of cognition and BDs based on PGx principles
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