Abbreviations: AD: Alzheimer’s disease; Ctrl: controls; LOAD: Late-onset Alzheimer disease; MCI: Mild cognitive impairment. * Only newly identified genes are shown. Furthermore, studies that have made associations between genetics and epigenetics through epigenome-wide assays should not be left aside. DNA methylation, an epigenetic modification, plays an important role in regulating gene expression and thus in a wide range of diseases and biological processes ^[54][177]. Interestingly, one of these analyses was conducted in a Mexican-American population with mild cognitive impairment (MCI) ^[55][62], finding various methylation regions between control and MCI patients, as well as some genes involved in neuronal death, metabolic dysfunction, and inflammatory processes. Highlighting that methylation is transgenerationally heritable and affected by environmental factors ^[54][56][177,178], these processes could explain not only the relationship of genetics with the disease, but also its relationship with environmental and lifestyle factors. For example, exposure to organophosphate pesticides has been shown to promote Tau hyperphosphorylation and microtubule dysfunction ^[57][179]. Likewise, it has been shown that the methylation of genes, including ABCA7, BIN1, SORL1, and SLC24A4 (previously described in Figure 2), were significantly associated with the pathological processing of Tau protein and Aβ peptide. In addition, it was demonstrated that histone acetyltransferase and histone deacetylase inhibitors could increase the level of histone acetylation, and thus have different beneficial effects on AD ^[58][180]: (i) improve the expression of genes related to memory; (ii) prevent cognitive degeneration; (iii) decrease the deposition of the Aβ peptide; and (iv) avoid hyperphosphorylation of the Tau protein and the NFT formation. Therefore, the identification of polymorphisms associated with multiple environmental factors through GWAS could favor the development of effective diagnostic and therapeutic strategies. However, GWAS present certain limitations ^[59][181]: (1) they eventually involve the entire genome in disease predisposition; (2) the identification of multiple loci without a clear mechanism can be uninformative and cause confusion with respect to AD; (3) the vast majority of GWAS focus on the European population and lack population stratification; and (4) the scarce data can lead to the fact that the heritability of diseases is not fully explained and therefore fail to detect epistasis in humans, which is the main component of the genetic architecture of complex traits ^[60][182]. Despite these limitations, as has been analyzed throughout the manuscript, GWAS have multiple benefits given their diverse clinical applications and allow the identification of new biological mechanisms as well as ethnic variations in the health-disease process. Similarly, GWAS should be promoted in understudied populations, with a different methodological and study design, larger sample sizes, with more clinical data, and extrapolating the associations identified to in silico and preclinical models to take full advantage of the potential this technology offers us. Notwithstanding the significant advances in our understanding of AD pathobiology through GWAS technology, we have yet to identify a disease-modifying therapy that has demonstrated efficacy in humans. Most of the research conducted over the past 30 years has focused on anti-Aβ therapies ^[61][183]; however, all clinical trials with anti-Aβ therapies have been unsuccessful ^[62][184]. There are several reasons why these therapies may have failed ^[16][61][16,183]: (i) they are administered too late in the course of the disease when neuronal damage has already become irreversible; (ii) the misfolding and accumulation of the Aβ peptide is not the only cause of neurodegeneration and therefore it is not clear whether the reduction of Aβ levels effectively treats the disease; and (iii) since Aβ is produced by multiple pathways, inhibiting its production is complex. Despite the factors listed above, an IgG1 Aβ monoclonal antibody recently proved effective in phase 3 clinical trials to reduce AD biomarkers and reduce cognitive decline ^[63][185] and has already been approved for the treatment of AD by the Federal Drug Administration (FDA) ^[64][186]. The multiple genes identified by GWAS support the various theories that have been postulated to explain the development of AD, some of them involved in more than one mechanism, such as PICALM, CLU, and CD2AP, among others (Figure 2 and Table 1). This supports the hypothesis that the disease and its treatment should be considered from the multiconvergent theory and not through isolated mechanisms. It has been proposed that our genetic program should protect us from diseases, such as AD by working better under the conditions under which it was designed ^[65][187]; however, multiple behavioral and environmental factors could play a greater role in the development of the disease than their consideration by single mechanisms. This becomes even more important due to the aforementioned fact that most therapies against a single mechanism continue to show limited success and, therefore, understanding the disease from a unified theory would improve the results of preventive and therapeutic measures. In this context, multiple pathway-directed therapies may be more effective in slowing or preventing the progression of AD. For example, combined therapy with anti-Tau drugs, such as anti-amyloids, has been suggested, as well as the combination of neuroprotective drugs with anti-inflammatory and anti-oxidative stress effects ^[66][188]. On the other hand, it should be noted that genetics is only one factor that can influence the treatment of AD, since other factors, such as age, general state of health, and stage of the disease, can also influence the efficacy of the treatment. Similarly, the use of more general approaches to prevent or delay the onset of AD, such as lifestyle interventions or changes to prevent or delay the onset of AD [12], could be useful: maintaining a healthy diet, engaging in regular physical activity, and participating in cognitively stimulating activities ^[67][68][69][189,190,191].