Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insufficient regulation for the generalized use of PGx in the clinical setting. The implementation of PGx requires: (i) education of physicians and all other parties involved in the use and benefits of PGx; (ii) prospective studies to demonstrate the benefits of PGx genotyping; (iii) standardization of PGx procedures and development of clinical guidelines; (iv) NGS and microarrays to cover genes with high PGx potential; and (v) new regulations for PGx-related drug development and PGx drug labelling.

Sirtuins (SIRT1-7) are NAD⁺-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.

The investigation of new alternatives for disease prevention through the application of findings from dietary and food biotechnology is an ongoing challenge for the scientific community. New nutritional trends and the need to meet social and health demands have inspired the concept of functional foods and nutraceuticals which, in addition to their overall nutritional value, present certain properties for the maintenance of health. However, these effects are not universal. Nutrigenetics describes how the genetic profile has an impact on the response of the body to bioactive food components by influencing their absorption, metabolism, and site of action. The EbioSea Program, for biomarine prospection, and the Blue Butterfly Program, for the screening of vegetable-derived bioproducts, have identified a new series of nutraceuticals, devoid of side effects at conventional doses, with genotype-dependent preventive and therapeutic activity. Nutrigenomics and nutrigenetics provide the opportunity to explore the inter-individual differences in the metabolism of and response to nutrients, achieving optimal results. This fact leads to the concept of personalized nutrition as opposed to public health nutrition. Consequently, the development and prescription of nutraceuticals according to the individual genetic profile is essential to improve their effectiveness in the prevention and natural treatment of prevalent diseases.

Neurodegenerative disorders (NDDs) are major health issues in Western countries. Despite significant efforts, no effective therapeutics for NDDs exist. Several drugs that target epigenetic mechanisms (epidrugs) have been recently developed for the treatment of NDDs, and several of these are currently being tested in clinical trials. Furthermore, various bioproducts have shown important biological effects for the potential prevention and treatment of these disorders. Here, we review the use of natural products as epidrugs to treat NDDs in order to explore the epigenetic effects and benefits of functional foods and natural bioproducts on neurodegeneration.

Alzheimer’s disease (AD) is a complex/multifactorial brain disorder involving hundreds of defective genes, epigenetic aberrations, cerebrovascular alterations, and environmental risk factors. The onset of the neurodegenerative process is triggered decades before the first symptoms appear, probably due to a combination of genomic and epigenetic phenomena. Therefore, the primary objective of any effective treatment is to intercept the disease process in its presymptomatic phases. Since the approval of acetylcholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine) and Memantine, between 1993 and 2003, no new drug was approved by the FDA until the advent of immunotherapy with Aducanumab in 2021 and Lecanemab in 2023. Over the past decade, more than 10,000 new compounds with potential action on some pathogenic components of AD have been tested. The limitations of these anti-AD treatments have stimulated the search for multi-target (MT) drugs. In recent years, more than 1000 drugs with potential MT function have been studied in AD models. MT drugs aim to address the complex and multifactorial nature of the disease. This approach has the potential to offer more comprehensive benefits than single-target therapies, which may be limited in their effectiveness due to the intricate pathology of AD. A strategy still unexplored is the combination of epigenetic drugs with MT agents. Another option could be biotechnological products with pleiotropic action, among which nosustrophine-like compounds could represent an attractive, although not definitive, example.