Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

Abstract

About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…The present results appear to indicate that the combination therapy used in this study, probably together with the lipid-lowering effects and anti-atherosclerotic properties of sardilipin [18,24,73] and the prometabolic activity of animon complex, exert a positive synergistic effect on brain function accompanied by a transient improvement in mental performance, lasting for about 9-12 months Figure 2. The effect of CDP-choline, either alone or in combination with donepezil, as well as the effects of sardilipin, are APOE-dependent [3,[18][19][20][21][22][23][24][25][26][27][28].…”

“…From studies designed to define APOE-related AD phenotypes, several conclusions can be drawn: (i) the age-at-onset is 5-10 years earlier in approximately 80% of AD cases harboring the APOE-4/4 genotype; brain atrophy and AD neuropathology is markedly increased in APOE-4/4>APOE-3/4>APOE-3/3; (xi) brain mapping activity shows a significant increase in slow wave activity in APOE-4/4 from early stages of the disease; (xii) brain hemodynamics, as reflected by reduced brain blood flow velocity and increased pulsatility and resistance indices, is significantly worse in APOE-4/4 (and in APOE-4 carriers in general, as compared with APOE-3 carriers); brain hypoperfusion and neocortical oxygenation is also more deficient in APOE-4 carriers; (xiii) lymphocyte apoptosis is markedly enhanced in APOE-4 carriers; (xiv) cognitive deterioration is faster in APOE-4/4 patients than in carriers of any other APOE genotype; (xv) in approximately 3-8% of the AD cases, the presence of some dementia-related metabolic dysfunctions accumulates more in APOE-4 carriers than in APOE-3 carriers; (xvi) some behavioral disturbances, alterations in circadian rhythm patterns, and mood disorders are slightly more frequent in APOE-4 carriers; (xvii) aortic and systemic atherosclerosis is also more frequent in APOE-4 carriers; (xviii) liver metabolism and transaminase activity also differ in APOE-4/4 with respect to other genotypes; (xix) hypertension and other cardiovascular risk factors also accumulate in APOE-4; and (xx) APOE-4/4 carriers are the poorest responders to conventional drugs. These 20 major phenotypic features clearly illustrate the biological disadvantage of APOE-4 homozygotes and the potential consequences that these patients may experience when they receive pharmacological treatment for AD and/or concomitant pathologies [1][2][3][4][5][18][19][20][21][22][23][24][25][26][27][28][29][30][77][78][79]. In our study, it is clear that APOE-4 carriers are the worst responders to conventional treatments Figures 3 and 4.…”

“…The effect of CDP-choline, either alone or in combination with donepezil, as well as the effects of sardilipin, are APOE-dependent [3,[18][19][20][21][22][23][24][25][26][27][28]. In our study, the administration of cholinesterase inhibitors was avoided in 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M order to eliminate distorting variability and side-effects associated with CYP2D6-related factors [25,27,75].…”

“…APOE-4 may influence AD pathology by interacting with APP metabolism and Aβ accumulation, enhancing hyperphosphorylation of tau protein and neurofibrillary tangles (NFT) formation, reducing choline acetyltransferase activity, increasing oxidative processes, modifying inflammation-related neuroimmunotrophic activity and glial activation, altering lipid metabolism, lipid transport and membrane biosynthesis in sprouting and synaptic remodeling, and inducing neuronal apoptosis [5,[18][19][20][21]. In addition, multiple studies over the past two decades have demonstrated that APOE variants may affect the therapeutic response to anti-dementia drugs [20][21][22][23][24][25][26][27][28][29][30].…”

The Pathogenic Component of the APOE-TOMM40 Region in Alzheimer’s disease: Its Implications in Metabolomics and Pharmacogenomics

“…APOE-4 may influence AD pathology by interacting with APP metabolism and Aβ accumulation, enhancing hyperphosphorylation of tau protein and neurofibrillary tangle (NFT) formation, reducing choline acetyltransferase activity, increasing oxidative processes, modifying inflammation-related neuroimmunotrophic activity and glial activation, altering lipid metabolism, lipid transport and membrane biosynthesis in sprouting and synaptic remodeling, and inducing neuronal apoptosis [1,[6][7][8]. In addition, multiple studies over the past two decades have demonstrated that APOE variants may affect the therapeutic response to anti-dementia drugs [9][10][11][12][13][14][15][16][17].…”