Dementia is defined as a significant decline in cognition that interferes with independence and daily functioning. China accounts for approximately 25% of the world’s population with dementia (Jia et al., 2020). Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia disorders, particularly Alzheimer’s disease (AD). Each year, approximately 10–15% of individuals with MCI develop dementia (Giau et al., 2019).

As elevated cholesterol in plasma has been linked to several health conditions, it may involve in the pathogenesis of MCI. For example, A large Chinese population-based study (n = 46,011) suggested hyperlipidemia as a risk factor for MCI (Jia et al., 2020). Another meta-analysis reported that elevated cholesterol levels in mid-life may increase the risk of cognitive impairment in late life, whereas higher levels of cholesterol in late life were not associated with dementia or cognitive impairment (Anstey et al., 2017). Thus, investigators believe that the relationship between cholesterol and MCI is age-dependent and mid-life hyperlipidemia is a risk factor for developing dementia or cognitive impairment at a later age.

In recent years, accumulating evidence suggests that remnant cholesterol (RC) in triglyceride-rich lipoproteins promotes residual atherosclerotic cardiovascular disease (ASCVD) risk after lowering low-density lipid cholesterol (LDL-C) to the recommended target (Saeed et al., 2018; Burnett et al., 2020; Langsted et al., 2020; Bruemmer and Cho, 2021; Chevli et al., 2022; Hao et al., 2022; Zheng et al., 2022). Remarkably, a large prevention study (n = 17,532) reported that RC predicts cardiovascular disease beyond LDL-C and apolipoprotein B in patients without known ASCVD (Quispe et al., 2021). RC is defined as total cholesterol (TC) minus LDL-C minus high-density lipid cholesterol (HDL-C). In the fasting state, RC includes very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), and RC in the non-fasting state is composed of these two lipoproteins plus chylomicron remnants. Furthermore, except for cardiovascular disease, several studies reported that RC could predict stroke, hypertension, nonalcoholic fatty liver disease, diabetes mellitus, and aortic valve stenosis (Kaltoft et al., 2020; Jansson Sigfrids et al., 2021; Qian et al., 2021; Chen et al., 2022; Hu et al., 2022; Huang et al., 2022; Li et al., 2022).

Considering the wide connection between the diseases above and MCI, we hypothesized that plasma RC levels were also related to MCI. Therefore, in this study, we examined the association between plasma RC and MCI incidence and the relationship between plasma RC and different domains of cognitive performance in MCI patients.

In this study, we examined the relationship between plasma RC and MCI. The main results were (1) MCI patients had a higher level of RC than cognitively healthy controls; (2) Plasma RC level was positively associated with MCI risk; (3) RC level was related to impaired cognitive performance among MCI patients.

The mechanism of the association between RC and MCI remains unknown but biologically plausible. Vascular cognitive impairment (VCI), caused by cerebrovascular or cardiovascular diseases, is the second most common neuropathology of MCI (Aronow and Ahn, 2002; Smith, 2017; Gu et al., 2019). Specifically, cerebrovascular and cardiovascular diseases contribute to VCI via multiple types of vascular brain injury (e.g., infarcts, hemorrhages, white matter lesions, enlarged perivascular spaces, altered white matter microarchitecture, and disrupted network connectivity) (Smith, 2017). RC could also take part in the pathology of amyloid-positive MCI (Sagare et al., 2012). Experiments on cell cultures and animal studies suggested that the accumulation of cholesterol in neurons contributes to amyloid deposition in the brain by accelerating the cleavage of amyloid precursor proteins into amyloidogenic components, whereas cholesterol is kept low in neurons may inhibit Aβ accumulation (Toro et al., 2014; Wang H. et al., 2021). Furthermore, Reed B and colleagues (Reed et al., 2014) reported an association between persons’ serum cholesterol levels and cerebral β-amyloid (Aβ), with Aβ quantified using carbon C11-labeled Pittsburgh Compound B positron emission tomography.

We also found a wide range of relationships of RC with different domains of cognition, including executive function, visuospatial skill, immediate memory, and sustained attention, except for delayed memory. The small sample size might cause the lack of association between RC and delayed memory. Other possibilities could be the predominantly frontal impairment due to microvascular pathology, which needs to be confirmed in future studies. Besides, in the present study, we did not find differences in TG, TC, HDL-C, and LDL-C between MCI patients and healthy controls. Similarly, in a Chinese population-based study of older adults(n = 184), investigators reported that serum HDL-C was negatively related to the likelihood of MCI, without finding differences in serum TG, TC, and LDL-C between MCI patients and healthy controls (Wang M. et al., 2021). Conversely, in another Chinese case–control study (n = 227), plasma TC, TG, and HDL-C levels were reported to be associated with the risk of MCI, whereas LDL-C was not significantly different between the MCI group and controls (He et al., 2016). The inconsistent results may be influenced by different inclusion/exclusion criteria, and sample sizes.

Several limitations need to be acknowledged in the present study. First, the small sample size may impact the robustness of the study, thus further larger studies are needed to provide robust evidence for the relationship between plasma RC and MCI. Second, since the study design was cross-sectional, any causality of RC with MCI could not be explored. Third, residual confounders may exist due to several unmeasured factors such as marital status, BMI, physical activity, and depression. Lastly, the findings should be generalized with caution when considering our participants were only recruited from the memory clinic, population-based studies are needed in the future to verify the findings.

In conclusion, to our best knowledge, this study is the first to identify a relationship between plasma remnant cholesterol and MCI. In addition, remnant cholesterol was associated with different domains of cognitive function in MCI patients. Larger longitudinal studies are needed in the future to confirm the results due to the small sample size.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by This study was approved by the Institutional Review Board (IRB) of The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University. All participants completed an informed consent form. The patients/participants provided their written informed consent to participate in this study.

QZ: conceptualization, methodology, software, investigation, formal analysis, and writing–original draft. XZ and YuC: data curation. GD: visualization and investigation. YiC and WY: resources and supervision. SH: visualization and writing–review and editing. MZ: conceptualization, funding acquisition, resources, supervision, and writing–review and editing. All authors contributed to the article and approved the submitted version.

This study was supported by the General Program of Jiangsu Commission of Health (H2019051); the Elderly Program of Jiangsu Commission of Health (LKZ2022016).

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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