The ABCB1 Transporter in Alzheimer’s Disease

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…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 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]. The genetic and epigenetic defects identified so far in AD include Mendelian mutations, susceptibility single-nucleotide polymorphisms (SNPs), mitochondrial DNA (mtDNA) mutations, and epigenetic changes.…”

The human histaminergic system in neuropsychiatric disorders

“…The reports on the alterations in the histaminergic system in AD vary (Table 1). Some studies reported a hyperactive histaminergic system during aging [42] and in AD [43,44] with increased CSF histamine levels and increased histamine metabolites in the frontal cortex, basal ganglia, and hippocampus [43,44]; others reported diminished histamine levels in AD (e.g., in the hippocampus, frontal, and temporal cortex [45,46]). In addition, a loss of large histaminergic neurons in the rostral TMN in AD was observed [47].…”

Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer’s Disease

“…Thus, the dopaminergic system is a key neurotransmitter system involved in AD. Another key neurotransmitter system implicated in AD is the histaminergic system [11][12][13][14][15] and GPCR histamine H3 receptors (H 3 R) are widely expressed in the CNS, particularly in the frontal cortex and hippocampus [16]. H 3 R antagonists are promising drugs for AD [17][18][19] but the exact mode of action is more complex than suspected.…”