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.