Genomics and pharmacogenomics of dementia

Abstract

Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1×N/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics.