Cholesterol is constantly attributed to neurodegenerative diseases including Alzheimer’s disease (AD). This is due to the association of high blood cholesterol and the consequences of cholesterol metabolism in these conditions. However the brain isolates itself from the peripheral cholesterol with the use of its impervious barrier, therefore how does cholesterol influence the brain? Converted into the oxidized form known as 27-hydroxycholesterol (27-OH), extracerebral cholesterol is able to circumvent this blood brain barrier and enter the brain’s refuge. Some studies point to the effect of this oxysterol on brain cells, indicating that this metabolite is more than a cholesterol intermediate. Herein, we dissect the role this cholesterol metabolite undertakes in the brain both in vitro and in vivo , while probing its influence on neurodegenerative diseases. In Paper I we elucidated the levels of 27-OH in both the cerebrospinal fluid (CSF) and plasma of mild cognitively impaired (MCI) and AD patients. In addition to correlating it to AD markers, we further investigated its relationship with the angiotensin-converting enzyme (ACE), which was increased in AD as previously described. Delving deeper uncovered 27-OH had more of a causal link than a mere correlation with the renin-angiotensin system (RAS) in the brain highlighted in Paper I and Paper II. This system, apart from being independent from the renal system, is involved in many processes in the brain including learning and memory. The repercussions of 27-OH on the brain RAS was further investigated in vivo in Paper II, in mice lacking the ability to produce 27-OH, and in humans. Furthermore, the effects of 27-OH were also observed in mice fed a high-fat diet, a connection that is further investigated in all the papers within this thesis. These results draw to attention the relationship between plasma cholesterol, hypert ension and neurodegeneration. In addition to affecting the spatial memory of mice, 27-OH reduced the levels of glucose uptake in their brains. ...