APOE-TOMM40 in the Pharmacogenomics of Dementia

Ramon Cacabelos

doi:10.4172/2153-0645.1000135

Abstract

Polymorphic variants present in the APOE-TOMM40 region (19q13.2) are implicated in Alzheimer’s disease (AD) and have been shown to modify disease risk, age at onset of symptoms, and the therapeutic response to conventional drugs. We have investigated the structure of the APOE-TOMM40 region and the influence of APOE and TOMM40 poly T variants (rs10524523) in the therapeutic response to a multifactorial treatment in 920 Spanish patients with AD. The frequencies of TOMM40 poly T genotypes were: 18.37% S/S, 7.83% S/L, 38.80% S/VL, 1.52% L/L, 7.17% L/VL, and 26.31% VL/VL. The most frequent APOE-TOMM40 associations were as follows: 82% APOE-3/3 with S/S, 63% with S/VL, and 40% with VL/VL; 90% APOE-3/4 with S/L, 57% with L/VL, and 43% with VL/VL; and 100% APOE-4/4 with L/L. Globally, the response rate was about 59%, with no difference between females and males. APOE-4 carriers were found to be the worst responders (45-56%) whereas APOE-3/3 carriers were the best responders (70%) for a transient period of cognitive improvement (<12 m). Among TOMM40 variants, S/S carriers were the best responders (70%), followed by S/VL (61%), VL/VL (57%), and L/VL carriers (51%). The worst responders were those patients harboring the L/L genotype (35%). Therefore, specific APOE-TOMM40 poly T variants exert a powerful influence on the therapeutic response to conventional treatments in AD.

Highlights

The genes involved in the pharmacogenomic response to drugs in Alzheimer’s disease (AD) fall into five major categories: (i) genes associated with AD pathogenesis and neurodegeneration (APP, PSEN1, PSEN2, microtubule-associated protein Tau (MAPT), PRNP, apolipoprotein E (APOE) and others); (ii) genes associated with the mechanism of action of drugs; (iii) genes associated with drug metabolism (phase I (CYPs) and phase II reactions (UGTs, NATs); (iv) genes associated with drug transporters (ABCs, SLCs); and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions (APOs, ILs, MTHFR, ACE, AGT, NOS, etc) [1,2,3,4]
In the present study we have investigated the structure of the APOETOMM40 region in Spanish patients with dementia, and the influence of polymorphic variants in this genomic segment on the therapeutic response to a multifactorial treatment adapted to the pathogenic profile of the patients
APOE-4 carriers are the worst responders and APOE-3 carriers are the best responders to conventional treatments

Summary

Introduction

The genes involved in the pharmacogenomic response to drugs in Alzheimer’s disease (AD) fall into five major categories: (i) genes associated with AD pathogenesis and neurodegeneration (APP, PSEN1, PSEN2, MAPT, PRNP, APOE and others); (ii) genes associated with the mechanism of action of drugs (enzymes, receptors, transmitters, messengers); (iii) genes associated with drug metabolism (phase I (CYPs) and phase II reactions (UGTs, NATs); (iv) genes associated with drug transporters (ABCs, SLCs); and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions (APOs, ILs, MTHFR, ACE, AGT, NOS, etc) [1,2,3,4]. Mendelian mutations affect genes directly linked to AD, including mutations in the amyloid beta precursor protein (APP) gene (21q21)(AD1), mutations in the presenilin 1 (PSEN1) gene (14q24.3)(AD3), and mutations in the presenilin 2 (PSEN2) gene (1q31-q42) (AD4) [5,6,7,8,9,10]. PSEN1 and PSEN2 are important determinants of γ-secretase activity responsible for proteolytic cleavage of APP and NOTCH receptor proteins. Mutations in exons 16 and 17 of the APP gene appear with a frequency of 0.30% and 0.78%, respectively, in AD patients. PSEN1, PSEN2, and Received April 24, 2014; Accepted June 27, 2014; Published July 04, 2014

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