Neurology Central

Pleiotropy and promiscuity in pharmacogenomics for the treatment of Alzheimer’s disease and related risk factors

Patients with Alzheimer’s disease are current consumers of polypharmacy with a high risk for drug–drug interactions. Antidementia drugs and other pharmacological treatments for vascular risk factors associated with dementia exert pleiotropic effects which are promiscuously regulated by different gene products. The aim of this review is to highlight the influence of genes involved in pharmacogenetics (i.e., pathogenic, mechanistic, metabolic, transporter and pleiotropic genes) as major determinants of response to treatment in Alzheimer’s disease. Patients harboring poor or ultrarapid geno-phenotypes display more irregular profiles in drug efficacy and safety than extensive or intermediate metabolizers. Polymorphic variants of genes associated with lipid metabolism influence the therapeutic response to hypolipemic agents. Understanding these effects is very useful for optimizing polytherapy in dementia.

Alzheimer’s disease (AD) is a major problem of health in developed countries and the most prevalent form of dementia, representing the sixth cause of death in the USA with an age-adjusted death rate of 25.4 per 100,000. Dementia is one of the most prevalent neurological disorders [1], with a prevalence of 1.8% at 65–69 years and 42.1% at 95–99 years of age [2] (annual incidence: 34.1 per 1000 persons >60 years of age) [3]. Genomic, epigenomic, cerebrovascular, metabolic and environmental factors are potentially involved in the pathogenesis of this neurodegenerative disorder. Phenotypically, AD is a syndrome with a neuropathological component characterized by classic hallmarks (i.e., senile plaques, neurofibrillary tangles, neuritic desarborization and neuronal loss), and a neurobehavioral component represented by cognitive deterioration, behavioral changes and functional decline, and an age- and sex-related biological component [4–6].

Click here to read the full review from Future Neurology.