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  • The beneficial treatment with several statins have been eval

    2023-01-24

    The beneficial treatment with several statins have been evaluated in AD patients (Kivipelto et al., 2005), with controversial results. It has been suggested that statins slow cognitive decline in mild to moderate AD (Miida et al., 2005). Treatment with atorvastatin, combined with other medications, improved the performance of AD patients in cognition and memory evaluation exams when compared to individuals treated with placebo treatment (Sparks et al., 2006). In a transgenic mouse model of AD, simvastatin improved memory and ameliorated inflammation (Tong et al., 2012, Huang et al., 2017). On the other side, some studies report no effect with the treatment of statins. Both atorvastatin (Feldman et al., 2010, Sun et al., 2012) and simvastatin (Sano et al., 2011) therapies did not improve cognition in patients with mild to moderate AD. Likewise, patients with probable AD treated with different statins for at least 6 months, in different clinical trials, did not improve cognition, measured by Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) or Mini Mental State Examination (MMSE) (McGuinness et al., 2014). There was also no difference in the levels of Aβ and tau in both CSF and plasma of AD patients after 12 weeks of simvastatin treatment when compared to baseline levels, before the treatment (Serrano-Pozo et al., 2010). In another study, AD patients taking statins to treat a lipid disorder exhibited improved cognition 6 weeks after interruption of treatment. The same cognitive parameters worsened again after 6 weeks of reinstatement of statin therapy (Padala et al., 2012). Taken together, some studies show a potential beneficial effect of cholesterol-lowering drugs in the treatment of AD, while other studies suggest that these drugs have no effect or even that they can worsen cognition.
    Inflammation in AD Historically, it was believed that deposition of proteins in the nrf2 inhibitor was the only triggering factor for AD; the inflammatory response would be a response to pathophysiological events. However, recent studies suggest the involvement of the immune system in the pathogenesis of AD (Krstic et al., 2012, Srinivasan et al., 2016). In some neurodegenerative disorders, such as multiple sclerosis, the adaptive immune response is crucial for the neuroinflammatory process (Dendrou et al., 2015). On the other hand, inflammation in AD primarily concerns the innate immune system, principally the CNS resident cells such as microglia and astrocytes (Orre et al., 2014). Peripheral immune events, however, are also reported in AD and participate in the pathophysiology of the disease. Inflammation and apoptotic pathway-related genes are downregulated in peripheral blood mononuclear cells (PBMCs) from patients with MCI and AD (Hanzel et al., 2014), suggesting that molecules produced by PBMCs might be possible biomarkers for the diagnosis of the disease. Indeed, it was demonstrated that PBMCs from elderly patients with AD exhibit higher basal levels of pro-inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1β, when compared with healthy individuals of the same age (Rocha et al., 2012). Another study found that serum of AD patients have higher levels of inflammatory cytokines, including IL-1β and nrf2 inhibitor IL-6, compared to healthy controls (Licastro et al., 2000). Furthermore, an increase in IL-12, IL-16, IL-18 and tissue growth factor (TGF)-β1 levels in patients with moderate and mild AD suggests a systemic response to the disease (Motta et al., 2007). Moreover, PBMCs from AD patients show increased IL-1β production after non-specific stimulus via anti-CD3/CD28 antibodies (Rocha et al., 2012). Participation of lymphoid lineage cells in AD has also been reported. Natural killer (NK) cells, which are associated with innate immune response, have a reduced activity in patients with the disease when compared with healthy subjects (Araga et al., 1991, Richartz-Salzburger et al., 2007). However, little is known about the molecular mechanisms of NK activity in the development of AD (Jadidi-Niaragh et al., 2012).