6. CYPs in Dementia
In dementia, as in any other CNS disorder, CYP genomics is a very important issue since in practice over 90% of patients with dementia are daily consumers of psychotropics. Furthermore, some acetylcholinesterase inhibitors (the most prescribed anti-dementia drugs worldwide) are metabolized via CYP enzymes [6,7,102]. CYP2D6, CYP2C19, CYP2C9 and CYP3A4/5 deserve special consideration.
The CYP2D6 enzyme, encoded by a gene that maps on 22q13.1-13.2, catalyzes the oxidative metabolism of over 100 clinically important and commonly prescribed drugs such as cholinesterase inhibitors, antidepressants, neuroleptics, opioids, some β-blockers, class I antiarrhythmics, analgesics and many other drug categories [181], acting as substrates, inhibitors or inducers with which many other drugs may potentially interact, this leading to the outcome of ADRs. The CYP2D6 locus is highly polymorphic, with over 100 different CYP2D6 alleles identified in the general population showing deficient (PM), normal (EM), intermediate (IM) or increased enzymatic activity (UM) [182,183]. Most individuals (>80%) are EMs; however, remarkable interethnic differences exist in the frequency of the PM and UM phenotypes among different societies all over the world [16,141,184]. On average, approximately 6.28% of the world population belongs to the PM category. Europeans (7.86%), Polynesians (7.27%), and Africans (6.73%) exhibit the highest rate of PMs, whereas Orientals (0.94%) show the lowest rate. The frequency of PMs among Middle Eastern populations, Asians, and Americans is in the range of 2-3%. CYP2D6 gene duplications are relatively infrequent among Northern Europeans, but in East Africa the frequency of alleles with duplication of CYP2D6 is as high as 29% [185]. 
The most frequent CYP2D6 alleles in the European population are as follows: CYP2D6*1 (wild-type)(normal), CYP2D6*2 (2850C > T) (normal), CYP2D6*3 (2549A > del) (inactive), CYP2D6*4 (1846G > A) (inactive), CYP2D6*5 (gene deletion) (inactive), CYP2D6*6 (1707T > del) (inactive), CYP2D6*7 (2935A > C) (inactive), CYP2D6*8 (1758G > T) (inactive),  CYP2D6*9 (2613-2615 delAGA) (partially active), CYP2D6*10 (100C > T) (partially active), CYP2D6*11 (883G > C) (inactive), CYP2D6*12 (124G > A) (inactive), CYP2D6*17 (1023C > T) (partially active), and CYP2D6 gene duplications (with increased or decreased enzymatic activity depending upon the alleles involved) [6,8,11,16].
In the Spanish population, where the mixture of ancestral cultures has occurred for centuries, the distribution of the CYP2D6 genotypes differentiates 4 major categories of CYP2D6-related metabolizer types: (i) Extensive Metabolizers (EM) (*1/*1, *1/*2,*1/*10); (ii) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10); (iii) Poor Metabolizers (PM) (*4/*4, *5/*5); and (iv) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl). In this sample we found 51.61% EMs, 32.26% IMs, 9.03% PMs, and 7.10% UMs [8,11,25,99,100,101,102,104]. In a more recent study with 1,637 subjects and 644 patients with AD we did not find any significant difference between AD cases and the general population (GP) [7]. A variation rate higher than 2% was only found in the EM-*1/*1 genotype which is more frequent in the GP than in AD. The proportion of EMs was 59.51% in GP and 57.76% in AD; IMs were 29% in GP and 31% in AD; PMs were 4.46% in GP and 5.27% in AD; and UMs were 6.23% in GP and 5.9% in AD [7]. No major differences between females and males were found in the GP group; however, in AD, EMs are more frequent in females than in males, and PMs are more frequent in males than in females, indicating that males might be at higher risk for developing ADRs [7].

6.1. Association of CYP2D6 Variants with Alzheimer’s Disease-Related Genes
We have also investigated the association of CYP2D6 genotypes with AD-related genes, such as APP, MAPT, APOE, PSEN1, PSEN2, A2M, ACE, AGT, FOS, and PRNP variants [7,11,99,100,101,102,103,104]. Homozygous APOE-2/2 (12.56%) and APOE-4/4 (12.50%) accumulate in UMs, and APOE-4/4 cases were also more frequent in PMs (6.66%) than in EMs (3.95%) or IMs (0%). PSEN1-1/1 genotypes were more frequent in EMs (45%), whereas PSEN-1/2 genotypes were over-represented in IMs (63.16%) and UMs (60%). The presence of the PSEN1-2/2 genotype was especially high in PMs (38.46%) and UMs (20%). A mutation in the PSEN2 gene exon 5 (PS2E5+) was markedly present in UMs (66.67%). About 100% of UMs were A2M-V100I-A/A, and the A2M-V100I-G/G genotype was absent in PMs and UMs. The A2M-I/I genotype was absent in UMs, and 100% of UMs were A2M-I/D and ACE-D/D. Homozygous mutations in the FOS gene (B/B) were also only present in UMs. AGT-T235T cases were absent in PMs, and the AGT-M174M genotype appeared in 100% of PMs. Likewise, the PRNP-M129M variant was present in 100% of PMs and UMs. These association studies clearly show that in PMs and UMs there is an accumulation of AD-related polymorphic variants of risk which might be responsible for the defective therapeutic responses currently seen in these AD clusters [11,99,100,101,102].

6.2. CYP2D6-Related Biochemical and Hemodynamic Phenotypes in Alzheimer’s Disease
It appears that different CYP2D6 variants, expressing EMs, IMs, PMs, and UMs, influence to some extent several biochemical parameters, liver function, and vascular hemodynamic parameters which might affect drug efficacy and safety. Blood glucose levels are found to be elevated in EMs (*1/*1 vs. *4/*10) and in some IMs (*4/*10 vs. *1xN/*4), whereas other IMs (*1/*5 vs. *4/*4) tend to show lower levels of glucose compared with PMs (*4/*4) or UMs (*1xN/*4). The highest levels of total-cholesterol are detected in the EMs with the CYP2D6*1/*10 genotype (vs. *1/*1, *1/*4 and *1xN/*1). The same pattern has been observed with regard to LDL-cholesterol levels, which are significantly higher in the EM-*1/*10. In general, both total cholesterol levels and LDL-cholesterol levels are higher in EMs (with a significant difference between *1/*1 and *1/*10), intermediate levels are seen in IMs, and much lower levels in PMs and UMs; and the opposite occurs with HDL-cholesterol levels, which on average appear much lower in EMs than in IMs, PMs, and UMs, with the highest levels detected in *1/*3 and *1xN/*4. The levels of triglycerides are highly variable among different CYP2D6 polymorphisms, with the highest levels present in IMs (*4/*10 vs. *4/*5 and *1xN/*1) [11,102,104]. These data clearly indicate that lipid metabolism can be influenced by CYP2D6 variants or that specific phenotypes determined by multiple lipid-related genomic clusters are necessary to confer the character of EMs and IMs. Another possibility might be that some lipid metabolism genotypes interact with CYP2D6-related enzyme products leading to the definition of the pheno-genotype of PMs and UMs. No significant changes in blood pressure values have been found among CYP2D6 genotypes; however, important differences became apparent in brain cerebrovascular hemodynamics. In general terms, the best cerebrovascular hemodynamic pattern is observed in EMs and PMs, with higher brain blood flow velocities and lower resistance and pulsatility indices, but differential phenotypic profiles are detectable among CYP2D6 genotypes. For instance, systolic blood flow velocities (Sv) in the left middle cerebral arteries (LMCA) of AD patients are significantly lower in *1/*10 EMs, with high total cholesterol and LDL-cholesterol levels, than in IMs (*4/*10); and diastolic velocities (Dv) also tend to be much lower in *1/*10 and especially in PMs (*4/*4) and UMs (*1xN/*4), whereas the best Dv is measured in *1/*5 IMs. More striking are the results of both the pulsatility index (PI = (Sv-Dv)/Mv) and resistance index (RI = (Sv-Dv)/Sv), which are worse in IMs and PMs than in EMs and UMs. These data taken together seem to indicate that CYP2D6-related AD PMs exhibit a poorer cerebrovascular function which might affect drug penetration into the brain with the consequent therapeutic implications [11,99,100,101,102,103,104].

6.3. Influence of CYP2D6 Genotypes on Liver Transaminase Activity
In order to elucidate whether or not CYP2D6-related variants may influence transaminase activity, we have studied the association of GOT, GPT, and GGT activity with the most prevalent CYP2D6 genotypes in AD [11,100,101,102]. Globally, UMs and PMs tend to show the highest GOT activity and IMs the lowest. Significant differences appear among different IM-related genotypes. The *10/*10 genotype exhibited the lowest GOT activity with marked differences as compared to UMs. GPT activity was significantly higher in PMs (*4/*4) than in EMs (*1/*10) or IMs (*1/*4, *1/*5). The lowest GPT activity was found in EMs and IMs. Striking differences have been found in GGT activity between PMs (*4/*4), which showed the highest levels, and EMs (*1/*1; *1/*10), IMs (*1/*5), or UMs (*1xN/*1) [102]. Interestingly enough, the *10/*10 genotype, with the lowest values of GOT and GPT, exhibited the second highest levels of GGT after *4/*4, probably indicating that CYP2D6-related enzymes differentially regulate drug metabolism and transaminase activity in the liver. These results are also clear in demonstrating the direct effect of CYP2D6 variants on transaminase activity [11,101,102].