In a recent article published in the Genes Journal, researchers discussed the significance of pharmacogenomics-based studies in the research for personalized therapeutics for dementia, including drugs targeting both cognitive and non-cognitive symptoms.
They discussed pharmacotherapy approaches for Alzheimer’s disease (AD), vascular dementia (VaD), frontotemporal disease (FTD), and Lewy body disease (LBD).
In addition, they compiled and presented all relevant information on the most common types of dementia, such as their underlying molecular mechanisms and closely associated genes.
Study: Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms. Image Credit: Katy Pack/Shutterstock.com
Background
Dementia is a complex progressive disorder represented by cognitive decline. Its non-cognitive or behavioral and psychological symptoms, collectively referred to as BPSD, add substantial heterogeneity to dementia. Dementia pathogenesis and clinical manifestation are complex and involve more than 200 genes.
Given its complexity, dementia patients, especially older ones, typically simultaneously receive six to 10 drugs per day for treating various somatic disorders and comorbidities apart from their cognitive and BPSD.
These mainly include psychotropic drugs, such as antipsychotics, antidepressants, and anticonvulsants. Additionally, patients with dementia take anxiolytics, hypnotic, and sedative drugs.
Indeed, no single pharmacotherapy provides a comprehensive long-term remedy for dementia. Drug intolerance, side effects, and non-compliance are also responsible for the partial effectiveness of dementia pharmacotherapy.
Moreover, interindividual genetic variations alter the pharmacokinetics and pharmacodynamics of dementia drugs.
Thus, several complementing approaches are needed to broaden the available options for managing this condition and enhance the quality of life for individuals with dementia.
Pharmacogenomics, which addresses the genome-wide interaction of many genes affecting drug efficacy and safety of dementia therapeutics, could help with patient stratification, resulting in more effective therapy and reduced drug adverse effects among dementia patients. However, so far, it has remained challenging to apply it to dementia patients.
Genetic basis of different types of dementia
The etiology of dementia is multifactorial and involves complex interactions of various genetic, environmental, and (epi)genetic factors.
For instance, mutations in the presenilin (PSEN) 1 and 2 and amyloid precursor protein (APP) genes account for less than 1% of rare forms of dominantly inherited early-onset AD.
Late-onset AD is more prevalent and is typically sporadic. Its most important genetic risk factor is gene coding for apolipoprotein E (APOE). Additional risk factors for late-onset AD are disintegrin and metalloproteinase 10 (ADAM10), triggering receptors expressed on myeloid cells-2 (TREM2), and phospholipase D3 (PLD3).
The mutations in the neurogenic locus notch homolog protein 3 (Notch-3) gene contribute significantly to VaD, the second most common type of dementia. Moreover, its risk factors align with that of stroke.
In LBD, aggregation of α-synuclein leads to the formation of Lewy bodies, a cognitive deficit that impairs executive functions, attentiveness, and visuospatial abilities.
In contrast to Parkinson's disease (PD), LBD manifests with sensitivity to rapid eye movement (REM) sleep behavior disorder. Even though genetics, age, and environmental factors likely play a role in LBD etiology, the exact cause of LBD remains elusive.
Approximately 40% of cases of FTD, another sporadic dementia,
have a familial origin, and genes implicated in its pathogenesis are granulin (GRN), microtubule-associated protein (MAPT), and chromosome 9 open reading frame 72 (C9ORF72). FTD includes clinical subtypes; however, its patients characteristically exhibit significant frontal and temporal lobe atrophy. Apart from the behavioral variant, FTD also has three language variants.
Therapeutic strategies in dementia
The primary focus of any dementia pharmacotherapy is treating the impairment of cholinergic and glutamatergic systems involved in cognitive dysfunctions triggered by AD and other types of dementia.
Notably, ~15–20% of AD patients display abnormal acetylcholinesterase (AChE) metabolism, with nearly 50% being ultra-rapid and the other 50% being slow metabolizers.
N-methyl-d-aspartate (NMDA) receptor antagonists, e.g., memantine and AChE inhibitors, e.g., donepezil, have received the Food and Drug Administration (FDA) approval for managing AD-related cognitive symptoms; however, they do not effectively slow down the progression of the disease.
In addition, evidence suggests that AChEIs help alleviate neuropsychiatric symptoms in LBD and PD patients.
Memantine is an effective monotherapy for moderate and severe AD, while it only minimally improves cognition in patients with VaD. However, it helps maintain the normal functioning of the glutamatergic system in AD patients and is also better tolerated than AChEIs, especially in combination with donepezil.
Some monoclonal antibodies have been shown to effectively slow down the progression of mild dementia due to AD, for example, aducanumab and lecanemab.
Since single-target therapeutics have remained ineffective in slowing the progression of dementia, several multi-target compounds are currently undergoing investigation for AD treatment.
For example, ladostigil. This AChEI and a monoamine oxidase inhibitors (MAO)-A and B inhibitor is a combination drug made from rivastigmine, the N-propargyl scaffold from an anti-parkinsonian drug, and rasagiline.
Studies have shown that non-pharmacological treatments, however, are also effective in treating cognitive dysfunctions in people with dementia.
Examples include sensory and multi-sensory stimulation, e.g., visual, olfactory, tactile, taste, and kinaesthetic stimulation delivered via art, aroma, light, music, and dance therapies.
Pharmacogenomics of anti-dementia drugs
Different cytochrome P450 2D6 (CYP2D6) genetic variants influence the safety and efficacy of donepezil, the most prescribed AChE inhibitor drug. CYP2D6 rs1080985 is the most studied polymorphism in studies evaluating the clinical efficiency of donepezil.
Its G allele defines the CYP2D6*2A variant, potentially associated with a higher drug metabolism rate. Poor metabolizers of CYP2D6, thus, show a 32% slower clearance rate of donepezil compared to ultra-rapid metabolizers.
Several other genes, e.g., ATP-binding cassette (ABC) transporters and apolipoprotein E (APOE), modulate the efficiency of donepezil.
Evidence also suggests a potential association between estrogen receptor 1 (ESR1) gene variants and the therapeutic effects of donepezil, especially ESR1 polymorphisms rs2234693 and rs9340799.
Likewise, the rs1803274 polymorphism of the butyrylcholinesterase (BCHE) gene or K-variant has been associated with poor treatment response in patients receiving donepezil.
Other studies evaluating this association, however, have found opposing results. A study by De Beaumont et al. demonstrated that carriers of APOE ɛ4 and BCHE K-variant show better response to donepezil.
Other potential candidates in the pharmacogenetics of donepezil are the polymorphisms in the cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) gene and rs662 related to paraoxonase-1 (PON-1).
The former likely affects acetylcholine binding to neuronal nicotinic acetylcholine receptors (nAChRs). At the same time, the latter was found in higher frequency in patients showing a good response to donepezil treatment.
Likewise, different gene variants of APOE, BCHE, presenilin, and UDP glucuronosyltransferase 2B7 (UGT2B7) genes explain the observed variability in rivastigmine efficiency.
Similarly, CYP2D6 genetic variants have been associated with galantamine treatment's outcome and side effects. Ma et al. found that CYP2D6*10 rs1065852 carriers reported fewer adverse side effects to galantamine and better treatment response.
Pharmacogenetic studies focused on galantamine efficacy have also highlighted the involvement of genetic variants of CHRNA7.
Unlike AChEIs, studies focused on the pharmacogenetics of memantine efficacy are fewer. However, studies have highlighted the role of genetic variants of membrane transporter genes in variability observed in memantine pharmacokinetics.
OvejeroBenito et al. investigated the association of 67 single nucleotide polymorphisms (SNPs) in 21 genes encoding for different neurotransmitter receptors, including CYP2D6 and ABCB1.
However, they found no significant association with memantine and donepezil pharmacokinetics or adverse drug reactions.
Pharmacogenomics of multifactorial dementia treatments
Pharmacogenomics-based studies have thoroughly described the therapeutic effects of multifactorial therapy related to APOE and CYP2D6 variants.
A study investigating the effects of APOE variants on multifactorial treatment found APOE 3/4 carriers as the best and APOE 4/4 carriers as the worst responders to multifactorial therapy.
Likewise, a study investigating the influence of CYP2D6 variants showed that CYP2D6-extensive and intermediate metabolizers were the best responders to multifactorial therapy.
Consequently, they showed improved cognition after a year, while CYP2D6-poor and ultra-rapid metabolizers showed no improvement in cognitive functions.
Two challenges of multifactorial therapy are the existing comorbidities of patients, which reverse or modify the effects of dementia therapy, and the side effects of dementia therapy, e.g., amyloid-related imaging abnormalities (ARIA) induced by aducanumab and lecanemab monoclonal antibody treatments.
Pharmacogenomics of antipsychotic, antidepressant, antiepileptic, anxiolytic, hypnotic, and sedative drugs
Collectively, antipsychotics, antidepressants, and anticonvulsants are called psychotropic drugs, and the majority of these are metabolized by enzymes of the cytochrome P450 family, e.g., CYP2B6, CYP2D6, and CYP3A4.
Similarly, these enzymes metabolize tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and most antiepileptic drugs.
Over 100 different alleles of CYP2D6 enzyme show deficient, normal, intermediate, or increased enzymatic activity against these classes of drugs, implying all patients need different dosages. Accordingly, 10-20% of Caucasians carrying defective CYP2D6 variants display aberrant metabolism of psychotropics.
Since more males than females are poor metabolizers of psychotropic drugs, they are at a higher risk of an adverse drug reaction.
In addition, the metabolism of these drugs also depends on groups of enzymes, receptors (serotonin receptors), transporters (ATP-binding cassettes), and channels (sodium channels), which are genetically variable.
Polymorphisms in the serotonin receptor gene (5HTR2A) are associated with a better response to clozapine, olanzapine, or risperidone, all atypical antipsychotics.
The prevalence rates of anxiety and sleep problems in dementia are high and require treatment with anxiolytics, hypnotics, and sedative pharmaceuticals.
Benzodiazepines are the most prescribed drugs for the treatment of dementia-related anxiety and sleep disorders.
The majority of benzodiazepines are metabolized by CYP2C19 and CYP3A4/5, with over 40 polymorphic variants of the CYP2C19 gene generating 35 enzyme isoforms with CYP2C19*2 to CYP2C19*8 alleles associated with poor metabolism of benzodiazepines.
Conversely, the CYP2C19*17 variant increases the activity of benzodiazepines. Studies have also implicated CYP1A2, CYP2C9, and CYP2B6 genes in the metabolism of benzodiazepines.
Structurally different from benzodiazepines but with a similar mechanism of action, Z-drugs have significant hypnotic effects, e.g., zolpidem and the cytochrome P450 family genes, e.g., CYP3A4 mediate its metabolism pathways.
Conclusions
Pharmacogenomics-based methods could help offer safer and more effective personalized medications for dementia patients in the future; however, that requires evaluation from a pharmacogenomic perspective on a case-by-case basis.
These methods could also facilitate the identification of early detection markers for dementia diagnosis and improve understanding of its underlying causes.
Response to genetic variations affecting dementia drug absorption, distribution, metabolism, and elimination (ADME) are established.
However, further studies should investigate the functional consequences of genetic polymorphisms in other crucial genes, including neurotransmitter receptors, transporters, etc.
Journal reference:
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Vuic, B.; Milos, T.; Tudor, L.; Nikolac Perkovic, M.; Konjevod, M.; Nedic Erjavec, G.; Farkas, V.; Uzun, S.; Mimica, N.; Svob Strac, D.(2023) Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms. Genes, 14, 2048. doi: https://doi.org/10.3390/genes14112048. https://www.mdpi.com/2073-4425/14/11/2048
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