Ramon Cacabelos
EuroEspes Biomedical Research Center, Spain
Title: Genotype-related vascular phenotype in dementia: Impact on the pharmacogenetic outcome
Biography
Biography: Ramon Cacabelos
Abstract
Over 80% of patients with dementia older than 75 years of age exhibit a clear cerebrovascular component characterized by brain hemodynamic alterations, microinfarcts or ischemic signs. In Alzheimer’s disease (AD) patients, hypertension (>25%), overweightness (>40%) or obesity (>20%), diabetes (25%), hypercholesterolemia (>40%), hypertriglyceridemia (20%), cardiovascular disorders (>40%), atherosclerosis (>60%) and metabolic deficits (>20%) are common concomitant disorders contributing to premature neurodegeneration. In a cohort of 1803 patients with AD and 1096 controls, several SNPs in genes associated with lipid metabolism (APOE, APOB, APOC3, CETP, LPL), endothelial function and hypertension (NOS3, ACE, AGT), immune response and inflammation (IL1B, IL6, IL6R, TNFA) and thrombosis (F2, F5, MTHFR) were investigated. Although no significant differences were found between AD and controls, except in the case of APOE (p<0.0001), different SNPs in these genes exert a pathogenic influence in vulnerable patients. The therapeutic response to conventional drugs in AD is genotype-specific. The APOE-TOMM40 region is a reference locus in the pharmacogenetics of AD. APOE-4 carriers are the worst responders and APOE-3 carriers are the best responders to drugs. TOMM40 poly T-S/S carriers are the best responders, VL/VL and S/VL carriers are intermediate responders and L/L carriers are the worst responders to treatment. Patients harboring a large (L) number of poly T repeats in intron 6 of the TOMM40 gene (L/L or S/L genotypes) in haplotypes associated with APOE-4 are the worst responders to treatment. CYP2D6, CYP2C9, CYP2C19 and CYP3A4/5 variants also influence the pharmacogenetic outcome in AD. Polypharmacy in AD requires a personalized intervention to optimize therapeutics.