In the present study, high HCY concentrations and low TC levels were closely related with the risk of developing dementia among Chinese elderly people. In view of the need for blood-based screening to identify people most at risk of developing this condition, our study has proposed a formula (including age, LDL-C, TC, HCY and number of comorbidities) as a predictive tool to screen out patients with a higher risk of developing dementia at the community level, thus providing the basis for further accurate diagnosis.
As a result of the analysis of the general characteristics of patients, we found that age was a risk factor that was uncontrollable. Age was clearly the biggest risk factor for developing dementia, and most patients with sporadic dementia start to get ill after the age of 65 years. Epidemiological studies [4] in different countries worldwide have confirmed that the incidence and prevalence of dementia increases with age. The results of a meta-analysis revealed that the incidence of dementia doubled every 10 years after the of age 60 years [25]. It is worth noting that dementia is not the inevitable result of aging, and aging itself is not the only reason for the development of dementia.
Vascular risk factors are considered to be important indicators of dementia prevention [26]. Since lipid components represent potential prevention targets that are relatively easy to modify, it is of great clinical importance to explore their relationship with the risk of dementia. To date, studies on any link between dyslipidemia and dementia have produced inconsistent results. The age at which a patient's blood lipid levels are measured, and the length of follow-up may explain these differences. High cholesterol levels were shown to increase the risk of dementia, primarily in studies that measured lipid levels in middle age and/or followed the subjects over time until late in their lives. In contrast, short-term follow-up blood lipid measurement studies of patients in old age or those who did not reach this age with the highest prevalence of dementia, either found no association [14, 27] or sometimes an inverse relationship with the risk of dementia [28, 29]. Our study found that TC was a protective factor for dementia in a large sample of elderly people, and that low TC levels increased the risk of developing dementia. Cholesterol is one of the most important components of neurons and is essential for the development and maintenance of neuronal plasticity and functions [30]. Low cholesterol concentrations may be a symptom of dementia progression [31] and may herald the onset of dementia [32]. Even a drop in the cholesterol concentration, 9 years before dementia developed, can affect the diagnosis [29]. Total cholesterol levels may be reduced over time, but the rate of decline was much greater in patients who eventually experienced impairment of cognition [33]. In addition, a high total cholesterol concentration is associated with a lower mortality of older people [34], and it can thus be speculated that raised cholesterol concentrations give rise to better health than in people who have low cholesterol levels. In particular, these people may have better liver functions because a low total cholesterol concentration may reflect liver disease [34]. Several studies in Chinese populations also support this view [35, 36].
Previously published literature has reported that high HCY levels are independent risk factors for cognitive dysfunction, cerebrovascular disease and atherosclerosis [37]. High levels of HCY have been linked with an elevated risk of individuals developing cardiovascular disease and all-cause deaths [38], but the relationship between HCY and dementia or cognitive deterioration has not been consistently demonstrated [39]. Our study found that high HCY concentrations is a risk factor for dementia, which is consistent with the results of previous domestic and foreign studies [40]. Increased HCY concentrations may be associated with cognitive decline and the mechanisms involved may be related to direct neurotoxic or cerebrovascular damage. An increased concentration of HCY induces a cascade stress response, leading to intracranial arteriolosclerosis, which eventually induces an insufficient cerebral blood supply that leads to atrophy of the brain. High HCY concentrations can improve the sensitivity of neurons to excitatory poisons, promote apoptosis of neurons, and affect nerve conduction [41]. Interestingly, a recent cross-sectional study [42] found that both low and high cholesterol concentrations might be harmful to cognitive health in people with normal HCY levels. However, in people with high HCY concentrations, homocysteine has an overwhelming effect on cognition, regardless of the cholesterol concentration. This finding suggests that cholesterol and homocysteine may interact in the cognitive functions of an aged population. Both cholesterol and HCY concentrations can effectively be controlled by existing drugs. In 2012, the US Food and Drug Administration (FDA) added possible cognitive adverse reactions (including memory problems) to statin prescription information [43]. In terms of the risk of dementia, the cholesterol-lowering drugs commonly used in the elderly should be taken with caution.
Dementia is a global epidemic and early detection of patients at risk of dementia has become an internationally recognized priority. Blood-based predictive indicators are attractive options in the clinic because they are safe, reliable, simple to use and less costly for screening. For the screening of AD, a number of blood-based biomarkers have initially demonstrated the efficacy of distinguishing AD from matched controls in the elderly. Neocortical Aβ (extracellular β-amyloid) burden (NAB) is a good predictor of the progress of AD. One study recommended predicted human NAB level measurements based on the molecular characteristics of blood (sensitivity: 79.6%, specificity: 82.4%, AUC: 87.6%) [44]. In addition, it was also found that the success rate of MMSE and 25(OH)D3 combination in predicting mild cognitive impairment (MCI) and AD reached 98% [45], suggesting that this combination can support the clinical diagnosis of MCI and mild medium and serious stages of AD. Our study has proposed a formula based on blood test indicators to predict dementia (sensitivity 87.4%, specificity 55.8%, AUC 79%). This formula is simple and easy to use. The blood test indicators (TC, LDL-C and HCY) contained in the formula are low-cost routine tests. The prediction formula can be used as a screening tool for a broad population at the community level to facilitate the identification of patients who could potentially benefit from further more invasive or more expensive confirmatory tests for diagnosis (such as cerebrospinal fluid analysis or PET).
There are a number of limitations to our research that should be considered. First, the patients in our study were all Han people who live in Shanghai. Although this study analyzed a large cohort of patients, caution is needed when extending our conclusions to patients of other races and cities. Second, we made no comparisons between the different clinical types and different levels of cognitive impairment of dementia. Third, there may be a reverse causal relationship between lipid levels and dementia, and patients with dementia may be more likely to suffer from eating disorders and malnutrition, which may lead to lower cholesterol levels in the body. Unfortunately, the design of a cross-sectional study makes it impossible to explore causality. Further prospective studies are needed to provide evidence of causality.
In conclusions, this real-world cross-sectional study of a large sample size found that high HCY concentrations and low TC concentrations were independent risk factors for dementia in elderly patients. The formula of age + LDLC + TC + HCY + number of comorbidities predicted dementia and may serve as a cost-effective tool for the early detection of those people at a risk of developing dementia, and who could benefit from further invasive or indeed expensive confirmatory tests.