Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

Abstract

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.

Figure 1

Distribution and frequency of APOE genotypes in patients with CNS disorders. C: controls; ANX: anxiety; DEP: depression; PSY: psychotic disorders; STR: stroke; AD: Alzheimer's disease; PAR: Parkinson's disease; ADHD: attention-deficit hyperactivity disorder; MIG: migraine; EPI: epilepsy; VD: vascular dementia; VE: vascular encephalopathy; MS: multiple sclerosis; CVI: cerebrovascular insufficiency; BT: brain tumors; CNN: cranial nerve neuropathies; MR: mental retardation; PTBS: posttraumatic brain injury syndrome. Source: R. Cacabelos. CIBE Database. EuroEspes Biomedical Research Center, Institute for CNS Disorders, Coruña, Spain.

Figure 2

APOE-related therapeutic response to a multifactorial therapy in patients with dementia. Cognitive performance (MMSE Score). Tb: basal MMSE score prior to treatment; Tt: MMSE score after 3 months of treatment in the total sample. E2/3b: basal MMSE score in APOE-2/3 carriers; E2/3t: MMSE score after treatment in APOE-2/3 carriers; E2/4b: Basal MMSE score in APOE-2/4 carriers; E2/4t: MMSE score after treatment in APOE-2/4 carriers; E3/3b: basal MMSE score in APOE-3/3 carriers; E3/3t: MMSE score after treatment in APOE-3/3 carriers; E3/4b: basal MMSE score in APOE-3/4 carriers; E3/4t: MMSE score after treatment in APOE-3/4 carriers; E4/4b: basal MMSE score in APOE-4/4 carriers; E4/4: MMSE score after treatment in APOE-4/4 carriers.

Figure 3

APOE-related systolic blood pressure response to a multifactorial therapy in patients with dementia. Tb: basal systolic blood pressure (SBP) prior to treatment; Tt: SBP after 3 months of treatment in the total sample. E2/3b: basal SBP in APOE-2/3 carriers; E2/3t: SBP after treatment in APOE-2/3 carriers; E2/4b: basal SBP in APOE-2/4 carriers; E2/4t: SBP after treatment in APOE-2/4 carriers; E3/3b: basal SBP in APOE-3/3 carriers; E3/3t: SBP after treatment in APOE-3/3 carriers; E3/4b: basal SBP in APOE-3/4 carriers; E3/4t: SBP after treatment in APOE-3/4 carriers; E4/4b: basal SBP in APOE-4/4 carriers; E4/4: SBP after treatment in APOE-4/4 carriers.

Figure 4

APOE-related changes in total cholesterol levels in patients with dementia treated with E-SAR-94010. Tb: basal total cholesterol (CHO) levels prior to treatment; Tt: CHO levels after 3 months of treatment in the total sample. E2/3b: basal CHO levels in APOE-2/3 carriers; E2/3t: CHO levels after treatment in APOE-2/3 carriers; E2/4b: basal CHO levels in APOE-2/4 carriers; E2/4t: CHO levels after treatment in APOE-2/4 carriers; E3/3b: basal CHO levels in APOE-3/3 carriers; E3/3t: CHO levels after treatment in APOE-3/3 carriers; E3/4b: basal CHO levels in APOE-3/4 carriers; E3/4t: CHO levels after treatment in APOE-3/4 carriers; E4/4b: basal CHO levels in APOE-4/4 carriers; E4/4: CHO levels after treatment in APOE-4/4 carriers.

Figure 5

APOE-related changes in LDL-cholesterol levels in patients with dementia treated with E-SAR-94010. Tb: basal LDL-cholesterol (LDL-CHO) levels prior to treatment; Tt: LDL-CHO levels after 3 months of treatment in the total sample. E2/3b: basal LDL-CHO levels in APOE-2/3 carriers; E2/3t: LDL-CHO levels after treatment in APOE-2/3 carriers; E2/4b: basal LDL-CHO levels in APOE-2/4 carriers; E2/4t: LDL-CHO levels after treatment in APOE-2/4 carriers; E3/3b: basal LDL-CHO levels in APOE-3/3 carriers; E3/3t: LDL-CHO levels after treatment in APOE-3/3 carriers; E3/4b: basal LDL-CHO levels in APOE-3/4 carriers; E3/4t: LDL-CHO levels after treatment in APOE-3/4 carriers; E4/4b: basal LDL-CHO levels in APOE-4/4 carriers; E4/4: LDL-CHO levels after treatment in APOE-4/4 carriers.

Figure 6

Distribution and frequency of CYP2D6 variants in patients with CNS disorders. C: controls; ANX: anxiety; DEP: depression; PSY: psychotic disorders; STR: stroke; AD: Alzheimer's disease; PAR: Parkinson's disease; ADHD: attention-deficit hyperactivity disorder; MIG: migraine; EPI: epilepsy; VD: vascular dementia; VE: vascular encephalopathy; MS: multiple sclerosis; CVI: cerebrovascular insufficiency; BT: brain tumors; CNN: cranial nerve neuropathies; MR: mental retardation; PTBS: posttraumatic brain injury syndrome. Source: R. Cacabelos. CIBE Database. EuroEspes Biomedical Research Center, Institute for CNS Disorders, Coruña, Spain.

Figure 7

Distribution and frequency of CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultrarapid metabolizers (UMs) in patients with different CNS disorders. C: controls; ANX: anxiety; DEP: depression; PSY: psychotic disorders; STR: stroke; AD: Alzheimer's disease; PAR: Parkinson's disease; ADHD: attention-deficit hyperactivity disorder; MIG: migraine; EPI: epilepsy; VD: vascular dementia; VE: vascular encephalopathy; MS: multiple sclerosis; CVI: cerebrovascular insufficiency; BT: brain tumors; CNN: cranial nerve neuropathies; MR: mental retardation; PTBS: posttraumatic brain injury syndrome. Source: R. Cacabelos. CIBE Database. EuroEspes Biomedical Research Center, Institute for CNS Disorders, Coruña, Spain.