Association of serum cholesterol with Parkinson's disease in a cohort of statin‐free individuals

Abstract Introduction The role of serum cholesterol in the pathogenesis of Parkinson's disease (PD) remains unclear. The objective of this study was to assess the association between serum cholesterol and PD in a cohort of statin‐free newly diagnosed PD patients. Methods This retrospective study used fasting lipid profiles obtained from 672 consecutive statin‐free newly diagnosed PD individuals and 540 controls. These PD individuals were identified from three medical institutions during 2017–2021, and the controls were identified from three physical examination centers during the same time period. Logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment of age, sex, and tobacco use history. Results Among 672 PD individuals, 112 were excluded in accordance with the current criteria, leaving 560 PD patients. The multivariate binary logistic regression analysis showed that LDL‐C was the only variable contributing to the occurrence of PD (OR 1.39, 95% CI: 1.07‐2.31, p < .001) after adjusting for age, sex, and tobacco use history; this association persisted following further adjustment for TC and HDL‐C. In the subgroup analysis of the adjusted results of LDL‐C after correcting for TC and HDL‐C, lower LDL‐C was associated with a higher risk of PD. Conclusion Among selected populations of statin‐free newly diagnosed PD individuals, low LDL‐C might be associated with the occurrence of PD.

management and help with elucidating causal pathways, as well as uncovering positive and negative correlations with other diseases (Aarsland et al., 2012). The mechanisms of neuronal death in PD are not fully understood, which makes exploring risk factors for PD challenging (Venkatesan et al., 2021;Wu et al., 2021). Furthermore, the nimiety of identified risk factors for developing PD makes it difficult to predict disease occurrence and development or to reflect its severity (Allam et al., 2003;Sawada et al., 2007). The progressive degeneration and loss of dopaminergic neurons from the nigrostriatal pathway, the Brain Behav. 2022;12:e2454.
wileyonlinelibrary.com/journal/brb3 1 of 6 https://doi.org/10.1002/brb3.2454 formation of Lewy bodies, and microgliosis may be crucial pathological changes in PD, which result in a remarkable decrease in dopamine levels in the striatum (Oliveira et al., 2021;Ye et al., 2021). The particular etiology associated with the interplay among ageing, genetic susceptibility, and environmental factors remains unknown, although the identification of novel predictors of PD is becoming a growing area of interest (Latourelle et al., 2017;Macleod & Counsell, 2016).
Ever-increasing evidence (Trupp et al., 2014;van Wamelen et al., 2021) supports a multifaceted interaction between genetic, biological, and molecular abnormalities. The etiologic and physiological factors that contribute to this identification of prediction in the evolution of PD have become the focus of PD. Serum cholesterol, ageing, genetic factors, and oxidative stress may be associated with the degeneration and loss of dopaminergic neurons (Gudala et al., 2013).

Statistical analysis
The distribution of baseline data was extracted from administrative records. The primary comparisons involved the outcomes of LDL-C, HDL-C, and TC tested in the PD group versus the outcomes tested in the control group. A comparison of continuous variables at baseline was executed using Student's t-tests for normally distributed variables and the Mann-Whitney U test for nonnormally distributed variables.
Comparisons of categorical variables at baseline were executed using the chi-square test or Fisher's exact test. Multivariate binary logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for LDL-C, HDL-C, and TC to assess the association between serum cholesterol levels and the risk of PD, adjusting for age (by 5-year groups from age ≥45 to < 80), sex, education, tobacco use history (never, current, and past), body mass index (BMI), and disease duration. The subgroup analysis on LDL-C was conducted using quartiles. All statistical analyses were performed using the Statistical Package for the Social Sciences version 26 (SPSS Inc., Chicago, Illinois).
A p-value <.05 was considered significant.

Demographic characteristics
We identified 672 consecutive statin-free, newly diagnosed PD individuals, of whom 112 were excluded according to the established Between February 1, 2017 and February 31, 2021, 672 consecutive statin-free newly-diagnosed Parkinson's disease (PD) individuals were identified from three medical institutions Group PD (n = 560) Group Control (n = 540) Reasons for exclusion (n = 112) -lacking patient characteristics (n = 12) -without documented parkinsonism (n = 12) -injury of the central nervous system attributed to trauma, tumour, infection, or hepatic encephalopathy (n = 11) -secondary parkinsonism (n = 8) -drug-induced parkinsonism (n = 9) -post encephalitic parkinsonism (n = 11) -unspecified degenerative disease of the basal ganglia (n = 6) -previous therapy of antiparkinson medication (n = 5) -atypical parkinsonism (n = 13) -rest tremor involving the neck/head or voice (n = 6) -poor or no response to levodopa (n = 7) -disability resulted from unknown causes (n = 6) -dementia precluding applicable informed consent (n = 6) F I G U R E 1 Flow diagram exhibiting methods for identification of participators to assess the association of serum cholesterol with Parkinson's disease (PD) in a cohort of statin-free newly diagnosed PD individuals, and reasons for exclusion inclusion/exclusion criteria, as shown in Figure 1. Therefore, 560 individuals were included for analysis. Five hundred forty healthy controls were available.

DISCUSSION
This retrospective study provides evidence that low LDL-C may be associated with a high occurrence of PD in a cohort of statin-free newly diagnosed individuals. As with previous studies (Huang et al., 2007;Kreisler et al., 2007), the current findings are constrained by the retrospective design, and causal inferences are lacking. The low incidence of PD in the population makes it challenging to initiate prospective trials to assess the relationship between cholesterol levels and PD. The sample size of this study was relatively small, which led to limited statistical capacity. However, this study may be the largest retrospective study to assess the association of serum cholesterol with PD in a cohort of statin-free individuals.
A growing but still particularly inadequate body of literature (de Lau et al., 2006) has assessed the association of serum cholesterol with PD and indicated that lower serum cholesterol attributed to LDL-C may be associated with a higher risk of PD. To date, published studies (Bao et al., 2018;Saedi et al., 2021) assessing the association of LDL-C with PD in a cohort of statin-free individuals remain limited and debated. Consistent with the current findings, Huang et al. (Huang et al., 2007) showed that low LDL-C may be associated with the occurrence of PD and with age-dependent changes in cognitive function.
Similarly, Sterling et al. (Sterling et al., 2016) assessed the association between baseline LDL-C and prospective changes in PD and showed that higher LDL-C may result in improved fine motor function. Identifiable cholesterol-cognitive relationships could be propelled by low LDL-C associated with PD (Garcia-Sanz et al., 2021). However, previous evidence (Rozani et al., 2018) also favors an association between high serum cholesterol and low PD occurrence, implying a favorable role of high serum cholesterol in delaying the occurrence of PD. Based on analogous premises, the results from DATATOP (Huang et al., 2011) showed that low LDL-C may be associated with the progression of PD.
Although serum cholesterol may have a certain influence on the occurrence and development of PD, low LDL-C may only be a trigger of PD (Gudala et al., 2013;Saedi et al., 2021). Hence, understanding the potential association between low LDL-C and PD may be more clinically valuable. The pathogenic mechanism of PD may be associated with the abnormal interaction of cholesterol with α-synuclein, instigating its detrimental aggregation and resulting in the loss of dopaminergic neurons (Garcia-Sanz et al., 2021;Jankovic, 2008). Previous studies (Garcia-Sanz et al., 2021;Gudala et al., 2013) have shown that intracellular cholesterol has a dual role of not only resisting lysosomal membrane permeabilization but also aggravating the accumulation of α-synuclein. The process of neurotransmitter release is regulated by α-synuclein (Garcia-Sanz et al., 2021). Accumulation of αsynuclein eventually leads to obstruction of neurotransmitter release (Gudala et al., 2013;Rozani et al., 2018). Likewise, the apolipoproteins Although results from previous reviews (Rozani et al., 2018;Saedi et al., 2021) have indicated a potential role of serum cholesterol in PD pathogenesis, the process of cholesterol metabolism is dynamic, accompanied by the formation of a large number of metabolites, and it is possible that one or more metabolites can lead to the occurrence of PD under specific conditions (Hu, 2010;Huang et al., 2007), which can well explain the sporadic epidemiology of PD. Based on this premise, it may be difficult to reach a consensus on the understanding of PD risk factors when analyzing only the pathological mechanism of PD (Huang et al., 2008). A meta-analysis of four case-control and cohort studies (Gudala et al., 2013)  is the raw material needed to trigger synapses, and antagonizing LDL-C receptors will block this biological process (Deischinger et al., 2021;Garcia-Sanz et al., 2021). Nevertheless, in undamaged PD cells, cholesterol is synthesized predominantly by astrocytes and is then transported to neurons through LDL-C receptors and ApoE (Garcia-Sanz et al., 2021;Gudala et al., 2013). Given the restricted ability of serum cholesterol to infiltrate the blood-brain barrier, brain cholesterol is produced predominantly de novo and is not directly associated with serum cholesterol levels (Deischinger et al., 2021;Gudala et al., 2013;Latourelle et al., 2017).
Several leading limitations should be emphasized. The retrospective design of the review and the subjects included in the study may have an effect on our results to a degree and prevent us from deducing any underlying association between serum cholesterol and the risk of PD.

CONCLUSION
The findings from the study may add to an increasing body of evidence that among selected populations of statin-free PD individuals, lower LDL-C tends to be associated with a higher risk of PD. Although the serum cholesterol-PD relationship remains under dispute, the relationship may be driven by multiple risk factors associated with PD. The reduction in serum cholesterol may be only an early warning, which may result from the disorder of brain cholesterol homeostasis. Even if the association between serum cholesterol and PD is causal, considering the adverse effects of LDL-C on cardiovascular and cerebrovascular diseases, establishing an applicable cholesterol target may be necessary. Future trials are merited to further validate these findings and explore the underlying mechanisms.

ACKNOWLEDGMENTS
We thank the study participants and their relatives and the clinical staff for their support and contribution to this study. This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS
YG participated in the data collection and prepared the manuscript.
BX and PW participated in the statistical analysis and the preparation of study protocols. NL provided guidance in analyzing the dataset and contributed to writing the manuscript. All authors read and approved the manuscript.

DATA AVAILABILITY STATEMENT
The data used to support the findings of this study are available from the corresponding author upon request.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2454