Postoperative delirium (POD) is one of the most common complications in patients after surgery. POD may bring about a decline in cognitive ability, impair environmental interpretation, attention-deficit disorder, and dyssomnia (1). Moreover, it can ultimately lead to adverse outcomes such as an increased incidence of postoperative complications, more extended hospital stays, increased medical costs, and increased postoperative mortality (2). In consequence, it is of great importance to explore the effective forecasting methods for POD occurrence.

Metabolic disorder of blood lipids is also familiar in senior citizens. Some researchers found that hemorheology was associated with cognitive decline (3). Hyperlipidemia can lead to abnormal deposition of lipids in vascular endothelium and formation of atherosclerosis, damage the blood-brain barrier, resulting in abnormal accumulation of lipids in the brain, finally leading to the occurrence of neurodegenerative diseases. Changes in lipid-related metabolism and transport levels played a role in the prediction of Alzheimer’s disease (AD) (4), and plasma lipid metabolism levels in patients with cognitive impairment were also apparent differences from those in the normal subjects (5). Furthermore, elevated plasma triglyceride levels precede Amyloid-beta (Aβ) protein deposition (6), the value of triglyceride in predicting the occurrence of AD is not negligible. Hypercholesterolemia can exacerbate Aβ protein deposition in animal models (7), while in humans, lowering cholesterol levels can reduce the Aβ burden and reduce AD occurrence (8). A Retrospective cohort study shows that high cholesterol increases the risk of dementia (9). Aβ abnormal deposition is proportional to neurotoxicity (10, 11), abnormally phosphorylated tau protein deposited in cells to can form neurofibrillary tangles, which all can cause neurodegeneration finally (12). It is a neurodegenerative disease with AD, and delirium pathophysiology is similar to AD (13, 14). For the time being, however, there is still a lack of studies concerning whether Aβ and tau could modulate the relationships of hemorheology with POD.

Thus, we aimed to investigate the relevance between lipid levels and POD, test whether the influences of lipids on delirium were mediated by POD core pathology. All these analyses were conducted based on the Perioperative Neurocognitive Disorder and Biomarker Lifestyle (PNDABLE) study.

As far as we are aware, the study is the first that reported the relationship including mediator effects between serum lipid and POD. We mainly screened out several POD core proteins as mediators. Of course, they played different mediating effects in the relationship between different serum lipoprotein and POD.

Cholesterol is an essential component of membranes and plasma lipoprotein, and it also plays an essential part in the accommodation of synaptic function and cell plasticity (17). An independent study (18) found that hypercholesterolemia caused memory impairment, inflammation response, and cholinergic dysfunction. Conversely, taking cholesterol-reducing medications can bring down the risk of neurocognitive-related diseases (19). Our findings indicate that cholesterol amounts altered was concerned with POD, and serum cholesterol was proportional to the severity of POD; that is, it is positively correlated with MDAS scores. Hypercholesterolemia leading to POD partly by Aβ₄₂, t-Tau, Aβ₄₂/t-Tau ratios, Aβ₄₂/p-Tau ratios, and Aβ₄₀/p-Tau ratios, explanation by mediation effects. Likewise, Umeda et al. found that hypercholesterolemia accelerates the accumulation of Aβ oligomers and resulting in memory impairment (20). It is universally recognized that reduced CSF Aβ₄₂ concentration reflects the accumulation of aggregated Aβ₄₂ in amyloid plaques in the brain (21). In patients with hip fracture, this group found lower CSF Aβ₄₂ levels and increased CSF t-Tau levels who developed delirium compared to the control group, the biomarkers remained significant after adjusting for age, gender, and Informant Questionnaire on Cognitive Decline in the Elderly score. This result is consistent with our findings. Some research has found that cholesterol amounts modification altered amyloid precursor protein (APP) and Aβ expression (22, 23). Cholesterol transcellular transportation was altered by Aβ, while inhibition of intracellular transport of cholesterol reduced cleavage of Aβ from APP in neurons (24, 25). Intracellular cholesterol plays a significant role in modulating tau phosphorylation and maintaining microtubule stability, the researchers found (26). Van der et al. (27) found that the effects of cholesterol on tau proteostasis are correlated with APP and Aβ. We also find this relationship by calculating the mediating effect. The interesting thing is that exercise can lower the tau pathology and its pathophysiological consequences (28). Exercise decreased the levels of soluble Aβ₄₀ and Aβ₄₂ (29), also reducing the lipid level in serum. It is tempting to think there is at least a case to be made for exercise to lower cholesterol levels and thus reduce the risk of POD.

Moreover, our results showed that triglyceride levels were higher than the NPOD group in POD patients, and the difference between the two groups has statistical significance. t-Tau, Aβ₄₂/t-Tau ratios, Aβ₄₀/t-Tau ratios, and Aβ₄₀/p-Tau ratios may mediate the effect of triglyceride on POD. Triglyceride components were found to be significantly associated with CSF Aβ₄₂ values (30). A longitudinal cohort study in cognitively healthy individuals concluded that increased levels of triglycerides could even predict CSF Aβ and tau pathology 20 years later (31). Higher serum triglyceride levels are associated with Parkinson’s disease mild cognitive impairment (32) and are one of the risk factors for AD (33). It was proved that triglycerides could cross the blood-brain barrier (BBB), consisting of human CSF, resulting in cognitive impairment (34). Some scholars have argued that the relation between triglycerides and cognition may be mediated by triglyceride regulation of the BBB transport of cognitively active gastrointestinal hormones (35). In animal models, an influential study showed that plasma triglyceride levels increased precede Aβ deposition (6), but total cholesterol levels were not significantly different in this research. In another model of hyperlipidemia-induced age-related neurodegeneration (36), chronic hypertriglyceridemia may lead to impaired neuronal function and neurodegeneration, possibly via hyperphosphorylation of tau protein, and this is similar to our findings.

More importantly, our analysis found that serum HDL level is associated with POD development, and high serum HDL level before surgery is one of the protective factors of POD. HDL-C is known as the “good cholesterol” because of its ability to reverse cholesterol transport. It protects against elevated lipid levels and protects against endothelial dysfunction, oxidative stress, inflammation, thrombosis, and more. Therefore, it is well known that serum HDL-C level is associated with a lower risk of cardiovascular disease. In addition, several studies have shown that individuals with higher levels of serum HDL-C is related to better cognitive function status (37–39), One possible reason is that HDL-C is capable of binding Aβ (40) and prevent Aβ aggregation into amyloid (41), and then improve clearance of Aβ from the brain, which in turn decreases the neurotoxicity of Aβ peptides (42). Another factor may be that serum HDL-C levels are inversely correlated with brain Aβ deposits (43). Our study did not support a significant mediation effect of Aβ deposits in the associations between serum HDL-C and MDAS, while the t-Tau, Aβ₄₀/t-Tau ratios, and Aβ₄₀/p-Tau ratios play full mediators on the relationship between HDL-C and MDAS. A study of older adults in China’s rural area showed that low HDL-C is associated with structural brain aging and cognitive dysfunction, but the association of low HDL-C with cognitive aging is not mediated by brain structure (44). Our data agree with previous research that low HDL-C is associated with cognitive impairment and dementia and is a risk factor for memory deficit and decline (45).

Our data insinuate that preoperative LDL-C levels were positively correlated with POD occurrence. Aβ₄₂ and t-Tau may mediate the effect of LDL-C on POD. In addition, Aβ₄₂ is a complete mediation. Our data support the view that a higher LDL-C level was associated with higher Aβ deposition and lower cognitive function (46, 47). In an Australian study, researchers discovered that higher levels of cholesterol and LDL-C were related to impaired processing speed, recognition memory, and working memory (48). However, in a prospective cohort study in Japan, higher LDL-C levels were associated with higher scores in memory performance after controlling for confounders (49), The Japanese study is broadly similar to the results of a cross-sectional study from China (50). According to the Chinese study, higher LDL-C was significantly negatively related to higher MMSE scores among the oldest old (aged 80 + years). Another Chinese study showed that a high level of LDL-C may be considered a potentially protective factor against cognition decline (51). Still, some research showed that LDL-C level did not influence the incidence of cognitive disorder or global cognitive performance (52, 53). All of the above studies come from different countries and regions, with different living standards and educational levels, so many factors influence the results. Therefore, future large-sample multicenter studies are needed to support the relationship between LDL-C and POD.

There are limitations to this study. As this is an observational cross-sectional design, we only tried to infer the causal relationship, but the specific relationship needs further study. In addition, our study only measured lipid levels at a one-time point before surgery, and more comprehensive monitoring of lipid levels is needed in the future. The research population we included come from the same hospital, which is also the deficiency of our experimental study. If possible, we hope to conduct verification of our experimental model in other independent and comparable hospitals in future studies.

To sum up, the present study indicated that the increase of serum TG, TC, and LDL-C concentration are risk factors for the development of POD, while high HDL-C concentration is a protective factor for POD, and the occurrence of POD caused by hyperlipidemia may be caused by POD core protein. Therefore, we advocate maintaining a healthy lifestyle to reduce lipid levels and thus reduce the incidence of POD.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Clinical Trial Ethics Committee of Qingdao Municipal Hospital. The patients/participants provided their written informed consent to participate in this study.

YL contributed to the statistical analysis, and manuscript preparation. XD, FL, and HT involved in the data collection and ELISA performance. XP, XL, and RD revised the manuscript. YB and BW conceived the current study. All authors have contributed to the manuscript revising and editing critically for important intellectual content and given final approval of the version and agreed to be accountable for all aspects of the work presented here, reviewed, and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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