Pharmacogenomics-based studies in the research for personalized therapeutics for dementia
By Neha MathurNov 8 2023Reviewed by Lily Ramsey, LLM 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.
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.
Moreover, interindividual genetic variations alter the pharmacokinetics and pharmacodynamics of dementia drugs. For instance, mutations in the presenilin 1 and 2 and amyloid precursor protein genes account for less than 1% of rare forms of dominantly inherited early-onset AD. In contrast to Parkinson's disease , LBD manifests with sensitivity to rapid eye movement sleep behavior disorder. Even though genetics, age, and environmental factors likely play a role in LBD etiology, the exact cause of LBD remains elusive.have a familial origin, and genes implicated in its pathogenesis are granulin , microtubule-associated protein , and chromosome 9 open reading frame 72 .
In addition, evidence suggests that AChEIs help alleviate neuropsychiatric symptoms in LBD and PD patients. For example, ladostigil. This AChEI and a monoamine oxidase inhibitors -A and B inhibitor is a combination drug made from rivastigmine, the N-propargyl scaffold from an anti-parkinsonian drug, and rasagiline.
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. 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.
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. However, they found no significant association with memantine and donepezil pharmacokinetics or adverse drug reactions.
Consequently, they showed improved cognition after a year, while CYP2D6-poor and ultra-rapid metabolizers showed no improvement in cognitive functions. 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.
The prevalence rates of anxiety and sleep problems in dementia are high and require treatment with anxiolytics, hypnotics, and sedative pharmaceuticals.
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