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Ramón Cacabelos

Ramón Cacabelos

Camilo José Cela University, Madrid, Spain.

Title: Pharmacogenetics of cerebrovascular and cardiovascular risk factors in dementia

Biography

Biography: Ramón Cacabelos

Abstract

"Alzheimer’s disease (AD) is a heterogeneous disorder with, at least, a tetravalent phenotype (neuropathological, neurobehavioral, age-related and gender-related components). Consequently, therapeutic intervention in dementia is polymodal, in order to modify the expression of all these complex phenotypes. AD patients present concomitant disorders including hypertension (20-30%), obesity (>20%), diabetes (24%), dyslipidemia (>40%), and metabolic disorders (>15%). Cardiovascular disorders (>40%), atherosclerosis (>60%), and different modalities of cerebrovascular damage (>60%) are frequent among patients with AD. Most of these concomitant anomalies may contribute to accelerate the dementia process. Pharmacogenetic studies in hypercholesterolemic patients with dementia treated with Atorvastatin (ATO) + LipoEsar (LIP) indicate that the therapeutic response to the combination of a conventional statin and a novel anti-atherosclerotic bioproduct is highly influenced by pathogenic and metabolic genes: (i) Cholesterol (CHO) levels are APOE-dependent. APOE-4/4 carriers exhibit the highest CHO levels. APOE-2/3, APOE-3/4 and APOE-4/4 carriers experience a gradual age-dependent decrease in CHO levels. (ii) The therapeutic response of CHO to ATO+LIP is APOE-dependent. APOE-3/3 and APOE-3/4 carriers are the best responders and APOE-2/4 and APOE-4/4 carriers are the worst responders. (iii) CYP2D6-EMs and IMs show a significant decrease in CHO levels in response to ATO+LIP, whereas PMs and UMs exhibit a poorer CHO lowering effect. (iv) CYP2C9-EMs and IMs effectively respond to ATO+LIP, and CYP2C9-PMs do not respond. (v) CYP2C19-EMs and IMs significantly respond to ATO+LIP, and PMs do not show any effect. (vi) CYP3A4/5-EMs show a significant decrease in CHO levels after one month of treatment with ATO+LIP. Over 80% of CYP3A4/5-EMs respond to ATO+LIP, with an almost complete normalization of CHO levels. The effect in IMs is spectacular, with over 90% of the patients experiencing a drastic reduction in CHO levels, and 60% of RMs do not respond at all. Most of these effects can be explained on a pharmacogenetic basis. "