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Pharmacogenomics of Alzheimer’s Disease: Novel Strategies for Drug Utilization and Development

  • Protocol
Pharmacogenomics in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2547))

Abstract

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 .

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Acknowledgments

The authors would like to thank their collaborators at the International Center of Neuroscience and Genomic Medicine for technical assistance.

Declaration of Interest

RC is President and stockholder of EuroEspes (Biomedical Research Center), EuroEspes Biotechnology, IABRA, and EuroEspes Publishing Co. NC is a shareholder of EuroEspes, S.A. The authors have no other relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed apart from those disclosed.

Funding

This article was funded by EuroEspes, S.A., and IABRA (International Agency for Brain Research and Aging).

Author information

Authors and Affiliations

  1. Department of Genomic Medicine, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain

    Ramón Cacabelos

  2. Department of Neuroscience, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain

    Vinogran Naidoo

  3. Department of Medical Epigenetics, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain

    Olaia Martínez-Iglesias

  4. Department of Medical Biochemistry, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain

    Lola Corzo

  5. Department of Medical Documentation, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain

    Natalia Cacabelos

  6. Department of Neuropsychology, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain

    Rocío Pego

  7. Department of Genomics and Pharmacogenomics, International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain

    Juan C. Carril

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  1. Ramón Cacabelos
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Corresponding author

Correspondence to Ramón Cacabelos .

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  1. PharmTao, Santa Clara, CA, USA

    Qing Yan

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Cacabelos, R. et al. (2022). Pharmacogenomics of Alzheimer’s Disease: Novel Strategies for Drug Utilization and Development. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology, vol 2547. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2573-6_13

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  • DOI: https://doi.org/10.1007/978-1-0716-2573-6_13

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2572-9

  • Online ISBN: 978-1-0716-2573-6

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