Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.


Genetic Determinants of Lipid Metabolism and Vascular Function
Among hundreds of genes potentially involved in AD pathogenesis and concomitant disorders (cardiovascular and cerebrovascular disorders, hypercholesterolemia, and hypertension), at least four categories of genes deserve special attention: (i) genes associated with lipid metabolism (APOB, APOC3, APOE, CETP, and LPL), (ii) genes associated with endothelial function and hypertension (NOS3, ACE, and AGT); (iii) genes associated with immune function and inflammation (IL1B, IL6, IL6R, and TNFA); and (iv) genes associated with thrombosis and coagulation (F2, F5, and MTHFR) [17,36,39].
Although differences in genotype distribution and frequencies of all these genes between patients with AD and control subjects are negligible, except in the case of APOE [39] (Figures 3 and 4), some of them may influence the pharmacogenetic outcome in the treatment of major risk factors for dementia, such as hypercholesterolemia, cardiovascular disorders, and hypertension [39][40][41][42][43]. Furthermore, many of these genes interact in pathogenic cascades contributing to alter blood pressure, brain cholesterol, and Aβ metabolism, subsequently accelerating neuronal death in AD. A clear example is the angiotensin-converting enzyme (ACE), which degrades Aβ, and ACE inhibitors that contribute to slow down cognitive decline. In fact, some SNPs in the ACE gene (rs1800764 and rs4291) are associated with cognitive modification and therapeutic response to anti-hypertensive treatment with ACE inhibitors [44].

Genetic Determinants of Lipid Metabolism and Vascular Function
Among hundreds of genes potentially involved in AD pathogenesis and concomitant disorders (cardiovascular and cerebrovascular disorders, hypercholesterolemia, and hypertension), at least four categories of genes deserve special attention: (i) genes associated with lipid metabolism (APOB, APOC3, APOE, CETP, and LPL), (ii) genes associated with endothelial function and hypertension (NOS3, ACE, and AGT); (iii) genes associated with immune function and inflammation (IL1B, IL6, IL6R, and TNFA); and (iv) genes associated with thrombosis and coagulation (F2, F5, and MTHFR) [17,36,39].
Although differences in genotype distribution and frequencies of all these genes between patients with AD and control subjects are negligible, except in the case of APOE [39] (Figures 3 and 4), some of them may influence the pharmacogenetic outcome in the treatment of major risk factors for dementia, such as hypercholesterolemia, cardiovascular disorders, and hypertension [39][40][41][42][43]. Furthermore, many of these genes interact in pathogenic cascades contributing to alter blood pressure, brain cholesterol, and Aβ metabolism, subsequently accelerating neuronal death in AD. A clear example is the angiotensin-converting enzyme (ACE), which degrades Aβ, and ACE inhibitors that contribute to slow down cognitive decline. In fact, some SNPs in the ACE gene (rs1800764 and rs4291) are associated with cognitive modification and therapeutic response to anti-hypertensive treatment with ACE inhibitors [44].

Pharmacogenetics of Hypercholesterolemia in Alzheimer's Disease
Alterations in cholesterol (CHO) metabolism are involved in AD pathogenesis and over 40% of AD patients are hypercholesterolemic. High CHO levels are also associated with vascular dementia [45]. It has been postulated that statins, prescribed as lipid-lowering drugs to patients at risk for cardiovascular conditions, may be beneficial in AD [46][47][48]. Statins are currently used in AD [9]; however, clinical evidence shows conflicting results and poor benefits [49][50][51][52]. The potential beneficial effect of statins and reduction in AD risk varied across statin molecules, sex, and race/ethnicity [53]. Other studies indicate that simvastatin exacerbates amyloid angiopathy [54]. In contrast, lovastatin might reduce Aβ levels in humans [55]. Some mechanisms by which simvastatin and atorvastatin might facilitate amyloid-β-protein degradation would be by increasing neprilysin secretion from astrocytes through activation of Mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/Erk1/2) pathways [56], regulation of cholesterol in lipid rafts, suppression of inflammation, and inhibition of oxidative stress [47]. The pleiotropic effects of statins (simvastatin, atorvastatin, cerivastatin, fluvastatin, pravastatin, and rosuvastatin) ( Table 1 are apparently APOE-independent; however, APOE is a fundamental factor in the regulation of lipid metabolism, and APOE variants influence the therapeutic effect of most hypolipemic compounds, including statins [8,10,17,36]. Cognitive deterioration shows a clear age-dependent profile in AD, with an average decline of 3-5 points/year (Mini-Mental State Examination (MMSE) score); however, total CHO levels do not appear to affect mental deterioration in AD [17]. Blood lipid levels also show a moderate age-dependent profile. In the GP, CHO levels tend to increase with age, reaching a plateau at 60-70 years of age and declining thereafter; however, CHO levels in AD tend to diminish in an age-related fashion, but in age-matched samples CHO levels tend to be higher in AD as compared to GP [17].
In a selected group of 933 AD patients, we constructed a pentagenic haplotype integrating all possible variants of the APOE + APOB + EPOC3 + CETP + LPL genes and identified 111 haplotypes (H) ( Figure 5) with differential basal CHO levels ( Figure 6). About 75% of these haplotypes in the AD population have a frequency below 1%, 10% have a frequency between 1% and 2%, 8% have a frequency between 2% and 5%, and only 4% of the haplotypes are present in more than 5% of AD patients [17]. The haplotypes most frequently found are H55 (33-CT-CC-AG-CC) (8.79%), H58        The results of APOE-related cholesterol response to hypolipemic treatment in hypercholesterolemic AD patients revealed that in absolute terms all APOE variants respond similarly (RR > 70%) to treatment, with a significant reduction in CHO levels (p < 0.001) ( Figure 7); however, genotype-related correlation analysis case by case ( Figure 8) and comparative correlation analyses of APOE variants show a clear differential APOE-related pattern of CHO response to treatment [17].
J. Pers. Med. 2018, 8, 3 12 of 35 The results of APOE-related cholesterol response to hypolipemic treatment in hypercholesterolemic AD patients revealed that in absolute terms all APOE variants respond similarly (RR > 70%) to treatment, with a significant reduction in CHO levels (p < 0.001) ( Figure 7); however, genotype-related correlation analysis case by case ( Figure 8) and comparative correlation analyses of APOE variants show a clear differential APOE-related pattern of CHO response to treatment [17].  Carriers of APOB-C/C, APOB-C/T, and APOB-T/T variants exhibit a similar response (RR > 80%), with a significant decrease in CHO levels after treatment ( Figure 9) and almost identical efficiency in comparative analyses. APOC3-C/C, APOC3-C/G, and APOC3-G/G carriers also respond similarly (p < 0.001) (RR > 80%) (Figure 10), with a differential comparative profile among APOC3 variants. CETP-A/A, CETP-A/G, and CETP-G/G carriers show an identical response (p < 0.001; RR > 80%) ( Figure 11), with insignificant variability in comparative studies among CETP variants. The same therapeutic response is observed in LPL-C/C, LPL-C/G, and LPL-G/G carriers (p < 0.001; RR > 80%) ( Figure 12); however, in this case, LPL-C/C are the best responders, LPL-C/G are intermediate responders, and LPL-G/G are the most heterogeneous responders [17].            CYP haplotype-related blood total CHO levels are very heterogeneous, but absolute values of total CHO among the most frequent haplotypes are almost identical. The histograms of frequency associated with CHO levels are qualitatively different among carriers of different CYP variants. Basal CHO levels are higher in AD patients harboring the CYP2D6-*1/*1 and *1xN/*1 genotypes than in the corresponding GP genotypes, but no differences have been found according to the EM, IM, PM, or UM condition. The therapeutic response according to SNPs of metabolic genes (CYP2D6, CYP2C9, CYP2C19, and CYP3A4/4) in hypercholesterolemic patients is variable and geno-phenotype-dependent. Although all CYP2D6 variants exhibit a positive response to treatment, significant differences have only been detected in 2D6-*1/*1, 2D6-*1/*4, and 2D6-*1/*6 carriers. In absolute values, CYP2D6 extensive, intermediate, poor, and ultra-rapid metabolizers behave in a similar manner with a significant reduction in CHO levels; however, the RR is different in EMs (81%), IMs (78%), PMs (84%), and UMs (90%), indicating a variable efficiency of CYP2D6 enzymes. The comparative analysis indicates that carriers of mutant enzymes (PMs > UMs), with limitations in drug metabolism, display a more efficient response to hypolipemic treatment [17]. No differences are present in basal CHO levels between the GP and AD patients related to CYP2C9 genotypes. CYP2C9-EMs, -IMs, and -PMs show a similar response, with lower RR (75%) in PMs as compared with EMs (81%) and IMs (82%), and a clear differential comparative profile. AD cases harboring the CYP2C19-*1/*2 genotype, corresponding to CYP2C19-IMs, exhibit higher basal CHO levels than their homologs in the GP. The CHO response among CYP2C19-EMs, IMs, PMs, and UMs is more variable, with PMs showing a deficient response in comparison to EMs, IMs, and UMs, and a clearly different behavioral profile, especially in PMs and UMs [17]. CYP3A4/5 geno-phenotypes in AD and GP show similar basal CHO levels. CYP3A4/5-RMs respond poorly to hypolipemic treatment, with the worst RR (66%), whereas CYP3A4/5-EMs and -IMs exhibit an excellent response (p < 0.001; RR > 80%) [17].
Most of these effects can, in part, be explained on a pharmacogenetic basis. It is obvious that a simple stratification of patients according to single genotypes is of poor value for a fine interpretation of pharmacogenetic results; however, the integration of gene clusters associated with specific phenotypes yields informative haplotypes with potential utility in pharmacogenetic studies. It is likely that thousands of genes are involved in CHO metabolism, and probably not a single gene plays an absolute dominant role over the others; however, some genes exert a powerful effect on other congeners associated with a specific pathogenic cascade (e.g., APOE in AD) or a pharmacogenetic pathway (e.g., APOE vs. CYPs in AD treatment with donepezil) [3,10,25,36,37]. The lipid-lowering effects and the anti-atherosclerotic properties of LipoEsar are APOE-dependent, with APOE-3 carriers acting as the best responders and APOE-4 carriers behaving as the worst responders [10,58].
Statins (·-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (HMGCR) inhibitors) are among the most prescribed drugs worldwide (Table 1). Inhibition of HMGCR results in decreased intrahepatic CHO synthesis, together with the upregulation of LDL-CHO receptors, increased LDL-CHO uptake by hepatocytes, and decreased levels of systemic LDL-CHO. The most relevant ADRs of statins are muscle, liver, and brain toxicity.
HMGCR variants (rs17244841, rs3846662, and rs17238540) (H7 haplotype) are responsible for an attenuated lipid-lowering response to statins [59,60]. Sex-related changes in cholesterol response to statins have been reported in carriers of the HMGCR-AA genotype at rs3846662, who have higher levels of total and LDL-cholesterol. The percentage reduction in LDL-cholesterol upon statin treatment is decreased in women with the AA genotype compared with women without it. In hypercholesterolemic patients, HMGCR alternative splicing may explain 22-55% of the variance in statin response [61].
Several polymorphisms in the SLCO1B1 gene may alter transport of statins into the liver. The SLCO1B1 521C (rs4149056) variant is associated with diminished effects of simvastatin, atorvastatin, lovastatin, and pravastatin [62]. Another transporter that modifies the effects of statins is ABCB1, especially in carriers of the ABCB1-1236T (rs1128503), 2677T (rs2032582), and 3435T (rs1045642) variants (TTT haplotype) [63]. Other transporters potentially affecting statin transport and metabolism include ABCC2, ABCG2, ABCB11, SLC15A1, SLC22A6, SLC22A8, SLCO2B1, SCLO1B3, and SLCO1B3 [59]. Statin metabolism is influenced by the following enzymes: CYP3A4/5, CYP2C8/9, CYP2C19, CYP2D6, UGT1A1, UGT1A3, and UGT2B7 [59]. The deficient CYP3A4 enzyme in CYP3A4*22 (rs35599367) carriers alters the pharmacokinetics and pharmacodynamics of simvastatin, atorvastatin, and lovastatin [64], and the CYP3A5*3 (rs776746) variant (loss-of-function allele) causes a high increase in the bioavailability of simvastatin [65,66]. The powerful effect of atorvastatin in CYP3A4/5-IMs is the result of a poor metabolization of atorvastatin by mutant CYP3A4/5 enzymes, since atorvastatin is a major substrate of CYP3A4/5. In contrast, the lack of effect in CYP3A4/5-RMs results from a rapid destruction of the drug in the liver mediated by excessive CYP3A4/5 enzymatic activity. Therefore, the dose of statins should be adjusted to the metabolizing condition of each patient to optimize the lipid-lowering effects of statins and to avoid toxicity [36,64]. Furthermore, the co-administration of the nutraceutical LipoEsar enhances the hypolipemic effect of atorvastatin and facilitates a dose reduction of the statin by 50%, minimizing potential ADRs in susceptible patients [10,16,17].
In our casuistic, we treated hypertensive AD patients with Enalapril (10-20 mg/day) for one month and performed a pharmacogenetic study assessing the potential influence of APOE, NOS3, ACE, AGT, and CYP2D6, 2C19, 2C9, and 3A4/5 variants on blood pressure response to this competitive inhibitor of the angiotensin-converting enzyme. In AD patients, SBP decreased from 139.44 ± 21.79 to 136.28 ± 21.13 mm Hg (p < 0.0001); and DBP decreased from 79.04 ± 11.02 to 77.78 ± 10.64 mm Hg (p = 0.004). A similar response was observed in hypertensive non-demented patients. Analysis of the genotype-related blood pressure response to APOE (Figure 14), NOS3 (Figure 15), ACE (Figure 16), and AGT variants ( Figure 17) revealed that specific polymorphisms in these genes differentially influence the hypotensive effect of Enalapril in AD patients. For instance, only APOE-3/3 and APOE-3/4 carriers responded with significant reductions in SBP (p < 0.001) and DBP values (p < 0.05) ( Figure 14); and APOE-4 carriers tended to show higher hypertensive levels than APOE-4 non-carriers ( Figure 14). NOS3-G/G carriers responded better than NOS3-G/T > NOS3-T/T carriers ( Figure 15). Polymorphic variants of the ACE rs4332 (547C>T) SNP did not show any effect; however, ACE-I/D carriers of the Alu 287 bp Indel I/D exhibited a better response than ACE-D/D and ACE-I/I carriers in SBP, and ACE-I/I carriers responded better in DBP than ACE-D/D and ACE-I/D ( Figure 16). Probably, the clearest response was observed among AGT-A/A and AGT-A/G carriers, who responded significantly better than AGT-G/G carriers ( Figure 17). Concerning CYP variants, CYP2D6-, CYP2C19-, and CYP2C9-EMs and -IMs are better responders that PMs or UMs. CYP3A4/5 variants did not show any effect on blood pressure changes. However, it is very likely that different CYP variants influence basal SBP and DBP values. In our casuistic, we treated hypertensive AD patients with Enalapril (10-20 mg/day) for one month and performed a pharmacogenetic study assessing the potential influence of APOE, NOS3, ACE, AGT, and CYP2D6, 2C19, 2C9, and 3A4/5 variants on blood pressure response to this competitive inhibitor of the angiotensin-converting enzyme. In AD patients, SBP decreased from 139.44 ± 21.79 to 136.28 ± 21.13 mm Hg (p < 0.0001); and DBP decreased from 79.04 ± 11.02 to 77.78 ± 10.64 mm Hg (p = 0.004). A similar response was observed in hypertensive non-demented patients. Analysis of the genotype-related blood pressure response to APOE (Figure 14), NOS3 (Figure 15), ACE (Figure 16), and AGT variants ( Figure 17) revealed that specific polymorphisms in these genes differentially influence the hypotensive effect of Enalapril in AD patients. For instance, only APOE-3/3 and APOE-3/4 carriers responded with significant reductions in SBP (p < 0.001) and DBP values (p < 0.05) ( Figure 14); and APOE-4 carriers tended to show higher hypertensive levels than APOE-4 non-carriers ( Figure 14). NOS3-G/G carriers responded better than NOS3-G/T>NOS3-T/T carriers (Figure 15). Polymorphic variants of the ACE rs4332 (547C>T) SNP did not show any effect; however, ACE-I/D carriers of the Alu 287 bp Indel I/D exhibited a better response than ACE-D/D and ACE-I/I carriers in SBP, and ACE-I/I carriers responded better in DBP than ACE-D/D and ACE-I/D (Figure 16). Probably, the clearest response was observed among AGT-A/A and AGT-A/G carriers, who responded significantly better than AGT-G/G carriers ( Figure 17). Concerning CYP variants, CYP2D6-, CYP2C19-, and CYP2C9-EMs and -IMs are better responders that PMs or UMs. CYP3A4/5 variants did not show any effect on blood pressure changes. However, it is very likely that different CYP variants influence basal SBP and DBP values.  Table 2. Pharmacological profile and pharmacogenetics of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists. Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower levels of angiotensin II, which causes an increase in plasma renin activity and a reduction in aldosterone secretion. By decreasing local angiotensin II production, ACE inhibitors may decrease vascular tone by reducing direct angiotensin II-induced vasoconstriction and/or angiotensin II-induced increases in sympathetic activity. In hypertensive patients, captopril reduces blood pressure by decreasing total peripheral resistance with no change or an increase in heart rate, stroke volume, or cardiac output (these effects are independent of pre-treatment blood pressure/cardiac output). Causes arterial and possibly venous dilation. In patients with congestive heart failure, captopril decreases total peripheral resistance, pulmonary vascular resistance, pulmonary capillary wedge pressure, and mean arterial and right atrial pressures (cardiac index, cardiac output, stroke volume, and exercise tolerance are increased; heart rate decreases or is unchanged). The drug may also cause regional redistribution of blood flow, principally increasing renal blood flow (glomerular filtration rate is usually unchanged) with slight or no increase in flow in the forearm or hepatic vasculature, respectively. The hypotensive effect of captopril persists longer than inhibition of ACE in blood (unknown whether ACE is inhibited longer in vascular endothelium than in blood). Captopril alone is apparently more effective in reducing blood pressure in high or normal renin hypertension. Serum prolactin concentration has been reported to increase during captopril therapy. Effect: Angiotensin-Converting Enzyme Inhibition. Antihypertensive Agent. Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower levels of angiotensin II, which causes an increase in plasma renin activity and a reduction in aldosterone secretion. By decreasing local angiotensin II production, ACE inhibitors may decrease vascular tone by reducing direct angiotensin II-induced vasoconstriction and/or angiotensin II-induced increases in sympathetic activity. In hypertensive patients, captopril reduces blood pressure by decreasing total peripheral resistance with no change or an increase in heart rate, stroke volume, or cardiac output (these effects are independent of pre-treatment blood pressure/cardiac output). Causes arterial and possibly venous dilation. In patients with congestive heart failure, captopril decreases total peripheral resistance, pulmonary vascular resistance, pulmonary capillary wedge pressure, and mean arterial and right atrial pressures (cardiac index, cardiac output, stroke volume, and exercise tolerance are increased; heart rate decreases or is unchanged). The drug may also cause regional redistribution of blood flow, principally increasing renal blood flow (glomerular filtration rate is usually unchanged) with slight or no increase in flow in the forearm or hepatic vasculature, respectively. The hypotensive effect of captopril persists longer than inhibition of ACE in blood (unknown whether ACE is inhibited longer in vascular endothelium than in blood). Captopril alone is apparently more effective in reducing blood pressure in high or normal renin hypertension. Serum prolactin concentration has been reported to increase during captopril therapy. Effect: Angiotensin-Converting Enzyme Inhibition. Antihypertensive Agent. Name: Captopril IUPAC Name: L-Proline, 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-Molecular Formula: C 9 H 15 NO 3 S Molecular Weight: 217.29 g/mol Mechanism: Competitive inhibitor of angiotensin-converting enzyme (ACE). Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower levels of angiotensin II, which causes an increase in plasma renin activity and a reduction in aldosterone secretion. By decreasing local angiotensin II production, ACE inhibitors may decrease vascular tone by reducing direct angiotensin II-induced vasoconstriction and/or angiotensin II-induced increases in sympathetic activity. In hypertensive patients, captopril reduces blood pressure by decreasing total peripheral resistance with no change or an increase in heart rate, stroke volume, or cardiac output (these effects are independent of pre-treatment blood pressure/cardiac output). Causes arterial and possibly venous dilation. In patients with congestive heart failure, captopril decreases total peripheral resistance, pulmonary vascular resistance, pulmonary capillary wedge pressure, and mean arterial and right atrial pressures (cardiac index, cardiac output, stroke volume, and exercise tolerance are increased; heart rate decreases or is unchanged). The drug may also cause regional redistribution of blood flow, principally increasing renal blood flow (glomerular filtration rate is usually unchanged) with slight or no increase in flow in the forearm or hepatic vasculature, respectively. The hypotensive effect of captopril persists longer than inhibition of ACE in blood (unknown whether ACE is inhibited longer in vascular endothelium than in blood). Captopril alone is apparently more effective in reducing blood pressure in high or normal renin hypertension. Serum prolactin concentration has been reported to increase during captopril therapy. Effect: Angiotensin-Converting Enzyme Inhibition. Antihypertensive Agent.             1)] is a competitive ACE inhibitor that prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower levels of angiotensin II, which causes an increase in plasma renin activity and a reduction in aldosterone secretion [36]. ACE, ADRB2, AGT, AGTR1, BDKRB2, and NOS3 are mechanistic genes that regulate the effects of Enalapril. Forty-eight genes show evidence of involvement in blood pressure regulation and 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2 have been reported, with new replication evidence for EBF2 and NFKBIA [69]. This ACE inhibitor is an apparent substrate of CYP3A4/5 enzymes and is transported

Concluding Remarks
According to the present examples and abundant data collected from the international literature [36], it seems clear that cardio-cerebrovascular risk factors, such as blood pressure changes, hypercholesterolemia, and heart disorders may contribute to exacerbating the disease process in AD patients. Most of these medical conditions require pharmacological intervention with drugs that can interact among themselves and with anti-dementia drugs as well. Additionally, the therapeutic response to conventional drugs is genotype-dependent, but routine pharmacogenetic studies are scarcely performed; and over 90% of AD patients simultaneously receive different types of drugs for concomitant disorders with a high risk of drug-drug interactions and ADRs. From a practical perspective, in order to help physicians in their daily clinical practice, the implementation of relatively simple protocols of pharmacogenetics would be of great utility [17]. Examples derived from the present results suggest (i) that the dose of anti-dementia drugs in APOE-4 carriers and in CYP2D6-PMs and CYP2D6-UMs be adjusted, (ii) that the dose of statins in CYP3A4-IMs be reduced and statins metabolized via CYP enzymes in CYP3A4-RMs avoided due to inefficacy, and (iii) that the dose of ACE inhibitors (or select a more effective anti-hypertensive agent) in APOE-4/4, NOS3-T/T, and GT-G/G carriers be adjusted.
Some reflections might be necessary for improving the multifactorial therapeutic intervention in a complex disorder such as AD: (i) a better characterization of the roles played in drug efficacy and safety by genes involved in the pharmacogenomic network is highly desirable; (ii) since most genes are under the influence of the epigenetic machinery, pharmacoepigenomics is becoming an attractive field that deserves special attention, and some epigenetic drugs might also be helpful in selected AD cases, although at present most epigenetic drugs pose technical problems (bioavailability, toxicity, and brain penetration) [26,34,76]; (iii) drug-drug interactions represent a problematic issue in over 80% of AD patients; to palliate this difficulty, simple pharmacogenetic protocols should be introduced in the clinical setting to help physicians in their daily prescription activity, to minimize ADRs; (iv) since the neurodegenerative process underlying AD neuropathology starts 20-30 years before the onset of the disease, novel therapeutics should be addressed to prevent premature neuronal death (symptomatic drugs have proven to be poorly effective), and a better knowledge of drugs with potential neurodegenerative effects after chronic treatments is also necessary to limit their inappropriate use; (v) specific biomarkers for AD are necessary in three different contexts: predictive markers before disease onset, early diagnosis in initial stages, and drug monitoring (in both preventive and/or therapeutic strategies); and (vi) educational programs are fundamental for physicians to be aware of the usefulness of pharmacogenomics to prescribe more accurately, to avoid adverse reactions and to optimize the limited therapeutic resources available for the treatment of dementia [8,16,17].