However a high triglyceride level was associated
However, a high triglyceride level was associated with dementia in a study with subjects aged ≥65 years (Raffaitin et al., 2009). In another study, the serum triglyceride levels of three different transgenic mouse strains mimicking AD were also evaluated within the progression of the pathology. In one of them, triglycerides were found increased in different time points, and in another one, this lipid was increased in the time point preceding the amyloid deposition. No differences in triglyceride levels were observed in the third strain evaluated (Burgess et al., 2006). Accordingly, it was also demonstrated that the overexpression of apolipoprotein B-100 (ApoB-100), which leads to a significant increase in plasma triglyceride levels, is involved in cerebrovascular lesions and AD-associated neurodegeneration (Bereczki et al., 2008). In another study, an accumulation of monounsaturated fatty Cy3 RNA within the forebrain neural stem cells in a murine transgenic model for AD was shown, accompanied by several lipid-related genetic changes. Among them, there are lipid-processing genes related to fatty-acid and triglyceride pathways (Hamilton and Fernandes, 2018). Induction of hyperlipidemia with high-fat diet (HFD) in mice lacking ApoE increases the accumulation of lipids in the hippocampus and the plasmatic levels of triglycerides, total cholesterol, LDL and HDL, what is accompanied by hippocampal amyloid deposition and apoptosis (Zhao et al., 2017). Metabolic syndrome (MetS), which is a cluster of cardiovascular risk factors, that includes obesity, dyslipidemias and diabetes, has been recently studied as a probable AD risk factor (Misiak et al., 2012, Kim and Feldman, 2015). Some data suggested that MetS is not associated with AD, although some of its components (e.g. dyslipidemias or diabetes) are (Raffaitin et al., 2009, Forti et al., 2010, Frisardi et al., 2010). However, other studies reported a connection between these two pathological conditions (Kim and Feldman, 2015). In this context, obesity, a component of MetS, can be accompanied by an increase in insulin resistance, which can cause diabetes and contribute to dyslipidemias. Furthermore, cognitive decline is associated with insulin resistance, since insulin plays an important role in learning and memory (Rios et al., 2014, Kim and Feldman, 2015). It was demonstrated that a western diet induces MetS in a transgenic rat model that mimics AD, and is associated with worsened cognition, increased Aβ accumulation in the hippocampus and reduced neuroprotection (Martino Adami et al., 2017). In the context of all the lipid-related diseases, the effect of the food consumption is extremely relevant, and it is important to mention that the consumption of HFD is a central risk factor for metabolic disorders linked to obesity and to dyslipidemia (Buettner et al., 2006, El Akoum et al., 2011). Some sources of lipids for HFDs, such as coconut oil, can worsen this condition, causing a higher increase in triglycerides levels (Buettner et al., 2006). A wide range of data show that HFDs induce neuroinflammation and cognitive decline in normal mice, between other cognitive changes (Pistell et al., 2010, Vinuesa et al., 2016, Wu et al., 2017), as well as hasten those conditions in AD models (Knight et al., 2014, Ettcheto et al., 2016, Theriault et al., 2016, Sah et al., 2017). HDF also increases AD biomarkers, impairs synaptic plasticity and induces insulin resistance in normal mice (Liu et al., 2015, Kothari et al., 2017). Long-term high-cholesterol diet exacerbates the alterations in the cerebral vasculature and BBB integrity (Loffler et al., 2016) and Aβ accumulation in the brain of transgenic mice, which leads to an increase in tau hyperphosphorylation (Czuba et al., 2017). However, in a tau pathology model, HDF does not increase the phosphorylation of this protein (Gratuze et al., 2016). Taken together, previously published studies show a relevant correlation between lipid-associated diseases, especially cholesterol dysfunctions, and the incidence of dementia, including AD. Taking this into account, several studies made an attempt to treat AD with cholesterol-lowering drugs. Long-term treatment with simvastatin and pravastatin improved memory function in mice submitted to a high-cholesterol diet (Ghodke et al., 2012). In addition, the cognitive impairment induced by either HFD or administration of intracerebroventricular (i.c.v.) injection of streptozotocin is attenuated by pitavastatin and simvastatin (Dalla et al., 2010). Finally, a drug that belongs to another class of cholesterol-lowering drug, ezetimibe, also improved memory deficit induced by HFD and i.c.v. injection of streptozotocin (Dalla et al., 2009).