Thus, to avoid the tremendous expense associated with such failures, it is necessary to develop human model systems in order to elucidate the cellular and molecular functions of genetic risk factors and validate the beneficial effects of candidate drugs on AD pathology. In this review, we further discuss how GWAS have expanded our knowledge of AD, as well as the directions of future AD research. 2. AD. We also review how genetic risk factors may interact with age-associated, progressive decreases in cognitive function in patients with AD. gene, which codes tau protein, are not linked to familial types of AD, suggesting that tauopathy may not be a central player in AD. Furthermore, mouse models with fAD CFM 4 mutations do not exhibit tau pathology in vivo [12,14]. The absence of tauopathy in fAD mouse models may be due to the short lifespan of mice, which may prevent the level of A accumulation necessary CFM 4 to induce tauopathy. Such discrepancies may also be due to species differences between mice and humans, as the tau splicing variants expressed in mice differ from those observed in humans. Indeed, one recent study reported that tau hyperphosphorylation, abnormal tau conformational changes, and neurodegeneration were present in the brains of fAD mice with transplanted human tau, but not in control animals . Studies involving human model systems including induced pluripotent stem cells (iPSCs) have also reported increased levels of phosphor-tau in neurons derived from the iPSCs of patients with fAD or CFM 4 sporadic AD (sAD) [37,38,39,40]. Such studies have further demonstrated that inhibiting A generation leads to a reduction of tau hyperphosphorylation in these cells . In this regard, although some therapeutic approaches target tau rather than A, their beneficial effects in patients with AD have yet to be clinically proven. Despite its prevalence, there is currently no effective treatment for AD, and clinical trials of drugs targeting A aggregation or tau hyperphosphorylation have been largely disappointing. Furthermore, AD diagnosis remains difficult. However, over the past century, researchers have uncovered a great deal about AD (Figure 1). Open in a separate window Figure 1 Genome-wide association studies (GWAS) have identified Alzheimers CFM 4 disease (AD)-associated genetic risk factors unique to humans, suggesting that cellular and molecular functional changes occur in the early stages of AD. Such studies have identified CFM 4 several signaling pathways that may be involved in AD, as well as the role of aging in pathological processes [21,41]. Improvements in next-generation sequencing techniques allow for whole-genome/exome sequencing and comparisons of genomic information between individuals. GWAS of patients with sAD (who usually experience late-stage onset) and healthy individuals have revealed that there are multiple single nucleotide polymorphisms (SNPs) that are highly and significantly associated with sAD [21,42]. These data suggest that, even in patients with LOAD, genetic risk factors may play a major role in disease onset and progression. Because AD is among the major neurodegenerative diseases associated with aging , most research to date has focused on pathological features in aged models. For example, in studies involving fAD mice, AD-associated pathology such as A accumulation, neuroinflammation, and cognitive impairment was investigated mostly in aged animals. However, recent research has identified a strong association between various SNPs and AD (even LOAD), suggesting that the early stages of AD are associated with alterations in cellular and molecular function, particularly in neural progenitors and newborn neurons. Nonetheless, aging remains one of the strongest risk factors for AD, given that the risk of disease onset significantly increases with age . In other words, even people with potential genetic risk factors for AD rarely develop the disease before 65 years of age. This suggests that AD pathogenesis may share some underlying mechanisms with aging-associated changes in the brain. GWAS have revealed not only variations in genes associated with APP metabolism and A generation, but also SNPs at genes associated with Rabbit Polyclonal to MOBKL2B other cellular functions including the immune response,.