Department of Genomic Medicine, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain.
Department of Neuroscience, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain.
Methods Mol Biol. 2022;2547:275-387. doi: 10.1007/978-1-0716-2573-6_13.
Alzheimer's disease (AD) is a priority health problem in developed countries with a high cost to society. Approximately 20% of direct costs are associated with pharmacological treatment. Over 90% of patients require multifactorial treatments, with risk of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) for the treatment of concomitant diseases such as hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60-90%), neuropsychiatric disorders (60-90%), and cancer (10%).For the past decades, pharmacological studies in search of potential treatments for AD focused on the following categories: neurotransmitter enhancers (11.38%), multitarget drugs (2.45%), anti-amyloid agents (13.30%), anti-tau agents (2.03%), natural products and derivatives (25.58%), novel synthetic drugs (8.13%), novel targets (5.66%), repository drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and other compounds (<1%).Pharmacogenetic studies have shown that the therapeutic response to drugs in AD is genotype-specific in close association with the gene clusters that constitute the pharmacogenetic machinery (pathogenic, mechanistic, metabolic, transporter, pleiotropic genes) under the regulatory control of epigenetic mechanisms (DNA methylation, histone/chromatin remodeling, microRNA regulation). Most AD patients (>60%) are carriers of over ten pathogenic genes. The genes that most frequently (>50%) accumulate pathogenic variants in the same AD case are A2M (54.38%), ACE (78.94%), BIN1 (57.89%), CLU (63.15%), CPZ (63.15%), LHFPL6 (52.63%), MS4A4E (50.87%), MS4A6A (63.15%), PICALM (54.38%), PRNP (80.7059), and PSEN1 (77.19%). There is also an accumulation of 15 to 26 defective pharmagenes in approximately 85% of AD patients. About 50% of AD patients are carriers of at least 20 mutant pharmagenes, and over 80% are deficient metabolizers for the most common drugs, which are metabolized via the CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 enzymes.The implementation of pharmacogenetics can help optimize drug development and the limited therapeutic resources available to treat AD, and personalize the use of anti-dementia drugs in combination with other medications for the treatment of concomitant disorders.
阿尔茨海默病（AD）是发达国家的一个重点健康问题，给社会带来了高昂的成本。大约 20%的直接成本与药物治疗有关。超过 90%的患者需要多因素治疗，同时伴有高血压（>25%）、肥胖（>70%）、2 型糖尿病（>25%）、高胆固醇血症（40%）、高三酰甘油血症（20%）、代谢综合征（20%）、肝胆疾病（15%）、内分泌/代谢紊乱（>20%）、心血管疾病（40%）、脑血管疾病（60-90%）、神经精神疾病（60-90%）和癌症（10%）等伴随疾病的药物不良反应（ADRs）和药物-药物相互作用（DDIs）风险。在过去的几十年中，寻找 AD 潜在治疗方法的药理学研究集中在以下几类：神经递质增强剂（11.38%）、多靶点药物（2.45%）、抗淀粉样蛋白制剂（13.30%）、抗 tau 制剂（2.03%）、天然产物及其衍生物（25.58%）、新型合成药物（8.13%）、新型靶标（5.66%）、储存药物（11.77%）、抗炎药物（1.20%）、神经保护肽（1.25%）、干细胞治疗（1.85%）、纳米载体/纳米治疗学（1.52%）和其他化合物（<1%）。
遗传药理学研究表明，AD 中药物的治疗反应与构成遗传药理学机制（致病、机制、代谢、转运蛋白、多效性基因）的基因簇密切相关，这些基因簇受表观遗传机制（DNA 甲基化、组蛋白/染色质重塑、微小 RNA 调控）的调控。大多数 AD 患者（>60%）是超过 10 个致病基因的携带者。在同一个 AD 病例中，最常（>50%）积累致病变异的基因是 A2M（54.38%）、ACE（78.94%）、BIN1（57.89%）、CLU（63.15%）、CPZ（63.15%）、LHFPL6（52.63%）、MS4A4E（50.87%）、MS4A6A（63.15%）、PICALM（54.38%）、PRNP（80.7059%）和 PSEN1（77.19%）。大约 85%的 AD 患者中还存在 15 到 26 个缺陷性药物基因的积累。大约 50%的 AD 患者至少携带 20 个突变药物基因，超过 80%的患者是最常见药物的代谢不良者，这些药物通过 CYP2D6、CYP2C9、CYP2C19 和 CYP3A4/5 酶代谢。
遗传药理学的实施可以帮助优化药物开发和有限的治疗 AD 的治疗资源，并实现抗痴呆药物与其他药物联合治疗伴随疾病的个体化应用。
