## 4 Discussion
### Alzheimer's Disease and Cardiovascular Risk Factors
#### 4.2.2 Hypercholesterolaemia and Alzheimer's Disease  
Elevated cholesterol is a well-established risk factor for cardiovascular disease. However, the relationship between cholesterol levels and AD is complex and challenging to fully elucidate [54]. Notably, our results obtained did not demonstrate a statistically significant association between AD and a clinical diagnosis of hypercholesterolemiaaemia in the analysed sample.  
However, when further exploring blood levels of total cholesterol in relation to AD, significant associations were observed, showing higher TG levels in the case group. In our study, hypercholesterolemia was defined based on medical history and individual interviews, which may have limited the accuracy of participant classification. It is possible that some individuals with elevated cholesterol levels had not been previously diagnosed or were undergoing statin treatment, which could have attenuated the association with AD. Furthermore, previous studies have indicated that the relationship between cholesterol and AD is more evident when evaluating levels in midlife, whereas in older ages, the influence of cholesterol may be modulated by other factors, such as the presence of comorbidities or the use of lipid-lowering medication. In this context, the finding of significantly higher TClevels in the CG suggests that other lipid parameters may play a more relevant role in the pathophysiology of AD.  
It should be noted that the association of elevated cholesterol has been observed especially with vascular dementia, not with AD [55]. However, over the decades, from 1990 to the present day, several studies exploring the possible association between hypercholesterolemia and AD have been carried out with divergent results. [PERSON] et al. [56] conducted one of the pioneering longitudinal studies on total serum cholesterol and AD in 1998. In this study, they used a sample of 444 participants aged 70-89 years, whose total cholesterol was measured over several decades. The results revealed that participants who developed AD showed elevated cholesterol concentrations in early measurements compared to participants who did not have dementia (\(p<0.0008\)). These findings suggest that individuals with a history of high cholesterol levels in middle age have an increased risk of developing AD [56]. Years later, authors [PERSON] et al. [57] investigated the association of hypercholesterolemia and AD neuropathology in 3508 subjects with both diseases. Their results showed that hypercholesterolemia was significantly associated with a higher burden of diffuse neuritic plaques (OR: 1.32) as well as more severe cerebral amyloid angiopathy (OR: 1.26), thus suggesting that hypercholesterolemiaaemia was associated with a higher severity of AD pathology. Following this line, two prospective studies indicated that hypercholesterolemiaaemia is significantly associated with long-term AD incidence [58; 59]. In this way, [PERSON] et al. [59] specified that hypercholesterolemia and HBP were associated with deficits in visual and memory abilities, verbal reasoning and visuospatial skills. Recently, [PERSON] et al. [60] have described a possible pathway between Provrote convertase subtilisin/kexin type 9 (PCSK9) and the development of AD, because PCSK9 is involved in controlling hypercholesterolemia by modulating levels of low-density lipoprotein (LDL), an established risk factor for the onset of the AD [54]. In addition, PCSK9 causes inflammation and oxidative stress, which alters the histology of the blood-brain barrier and induces the onset of AD. This would imply that PCSK9 stimulates neurodegeneration, because PCSK9 has been found to be expressed in AD by neurons and glia cells [61].