Exploring the causal effects of serum lipids and lipidomes on lewy body dementia: a Mendelian randomization study

Lewy body dementia (LBD) is a neurodegenerative disease, which is the second most common form of clinical dementia after Alzheimer’s disease, accounting for 4-8% of all dementia cases (1, 2). The formation of Lewy bodies, which are intracellular deposits that form in dopaminergic neurons of the central nervous system, is a unique pathological feature of LBD (3). The primary constituent of Lewy bodies is the misfolded, aggregated form of alpha-synuclein (αS), which is found in pathogenic inclusions (4). The main clinical features of LBD include early fluctuations in attention, hallucinations, and Parkinson’s syndrome (5). Existing studies have shown that LBD occurs in elderly individuals, with the majority of patients presenting with clinical symptoms between the ages of 70 and 85 years (6). The aging of the world population is increasing rapidly, the number of patients with LBD will continue to increase, creating a greater demand for care and a growing burden on health care resources globally (3). Therefore, an in-depth investigation of the pathogenesis of LBD and the identification of potential risk factors for LBD are imperative.

There is a special isoform of LBD, called the apolipoprotein E (APOE) allele-carrying LBD isoforms. The apolipoprotein E (APOE) gene, which is involved in lipid transport and metabolism, mainly has three different alleles (APOE2, APOE3, APOE4) in human being (7). In particular, carriers of the APOE4 allele are usually prone to lipid metabolism disorders are therefore more susceptible to other diseases (8–10). The most common diseases associated with APOE4 allele include Alzheimer’s disease and cardiovascular disease (11). Furthermore, recent studies have indicated that the APOE4 allele status in Parkinson’s disease (PD) may be an important predictor of cognitive decline in Parkinson’s disease, its effect appears to be independent of gender, as in the findings of Umeh et al. (12). In addition, increased aggregation of αS proteins in the brains of LBD patients is strongly associated with carrying the APOE4 allele (13). However, to date, no study has clearly demonstrated the potential relationship between lipids and disease risk in LBD patients carrying the APOE4 allele or whether this potential relationship is associated with abnormal changes in the αS protein.

Recently, serum lipid levels have been shown to be associated with the occurrence and development of LBD. In a previous cross-sectional study, it was found that higher serum low-density lipoprotein cholesterol (LDL-C) concentration and lower high-density lipoprotein cholesterol (HDL-C) concentration will lead to an increased risk of LBD (14). Another Mendelian randomization (MR) study also confirmed the positive genetic causal effect of serum LDL-C level on the LBD risk (15). However, the existing studies included fewer types of lipids and did not comprehensively explore lipids composition. Lipidome components such as phospholipids and cholesterol are major sources of cell membrane components. Changes in cell membrane components have been shown to promote the aggregation of αS into amyloidogenic fibrils (16). Studies demonstrates that specific lipid fractions may also have an important part to play in the pathogenesis of LBD (17). However, few research studies have investigated the link between lipid fractions and LBD.

MR is predominantly used to explore causal relationships between exposures phenotypes and outcomes phenotypes from a genetic perspective. It can minimize the impact of confounders and the interference of negative causal effects (18, 19). Preliminary research has been conducted in previous studies to examine the effect of common lipids on the Lewy bodies dementia, but these studies remain incomplete. Therefore, the present study used a two-sample MR (TSMR) approach and try to provide insight into the causal effects of eight lipids and liposomes subdivided into 179 subfractions on LBD and its APOE4 gene-carrying subtypes. Hope the results could be instrumental for risk prediction, early prevention, and precision targeted therapy for LBD and its subtypes.

This is the first study to systematically assess the causal relationship between in vivo lipids, lipid composition and the risk of LBD and LBD with APOE4 alleles. First, our findings suggest that higher LDL-C and RC levels significant cause an increased risk of LBD. Second, among the LBD subtypes of APOE4 gene carriers, only RC levels have a causal positive relationship. Third, elevated levels of PC (18:1_20:4) increase the risk of LBD, while elevated levels of PC (O-16:0 20:4) and PC (O-18:1_20:4) have protective effect for LBD. Fourth, for LBD patients with APOE4 alleles, elevated levels of PC (16:1 18:0) and PC (O-18:2_18:1) lead to an increased risk, and elevated levels of PC (O-16:1_18:0), PEO (O-18:2_18:1), SM (d38:2), and TAG (56:5) significantly reduce the risk. Our study reveals the causal effects of multiple lipids on LBD and its APOE4 subtypes, enriching researchers’ understanding of lipids in the pathogenesis of LBD disease.

The results of the present study are consistent with the findings of previous studies showing that elevated LDL-C and RC levels are positively and causally associated with the development of LBD (15). Previous studies have shown that the vast majority of cholesterol in the brain is normally produced by astrocytes and oligodendrocytes. The blood-brain barrier (BBB) prevents potentially neurotoxic peripheral serum cholesterol from entering the brain, thus protecting neuronal function (27). In patients with hypercholesterolemia, researchers have observed an increase in serum–brain barrier permeability with increasing serum cholesterol concentrations, including LDL-C and RC, to cross the serum–brain barrier and enter and accumulate in the central nervous system (28, 29). Since the brain is unable to degrade cholesterol, this excess cholesterol is mainly excreted by oxidizing cholesterol to produce oxysterols. Among these, 27-hydroxycholesterol (27-OHC), a class of oxysterols, plays an important role in promoting the aggregation and diffusion of αS (30, 31). The abnormal aggregation of αS is usually considered one of the main pathological features of LBD. In contrast, we did not observe any causal relationship between LDL-C and APOE4 allele-carrying LBD, and elevated RC levels were the only risk factor for APOE4-carrying LBD. This finding suggested that LDL-C is not a risk factor for neurodegenerative diseases in individuals with APOE4 carriage but is only an independent risk factor for LBD risk. This conclusion is supported by a recent study that concluded that elevated RC levels have a potentially stronger role in APOE4-associated dementia risk than do common lipid components (e.g., TC and LDL-C). In addition, another study showed that LDL-C is similarly unrelated to APOE genotypes in the pathophysiology of Alzheimer’s disease (32). However, the exact mechanisms need to be further investigated (33).

The interpretation of the causal effect of lipid composition on LBD and the APOE4 gene is more complex and involves mainly the interaction of αS with the lipid components of phospholipid membranes (34). When αS binds and interacts with lipid membranes, αS undergoes a conformational change, i.e., the formation of insoluble oligomers by increasing the α-helix content, which in turn leads to the development of LBD (35). Many studies have shown that the relationship between the action of αS and lipid membranes depends on the lipid composition of the membrane, and our findings provide strong support for this view. PC, one of the most abundant phospholipids in cell membranes, has the complex effect on LBD and APOE4 allele-carrying LBD in this study. The presence of PC resulted in a decreased parallel β-folds in the secondary structures of oligomers, while the number of α-helices and disordered protein secondary structures increased. The interaction between αS and PC may also alter the structure and function of cell membranes (36). And in a lipidomic study of Parkinson’s disease, which cerebrospinal fluid from patients with PD was shown to contain increased levels of PCs, including PC (O-18:3_20:3), PC (14:0_18:2) and PC (O-20:2_24:3) (37). Our findings also revealed that in the case of APOE4 allele carriage, the presence of other phospholipids, including PIs and SMs may also be closely associated with the pathogenesis of disease. SMs are implicated in the pathogenesis of αS, leading to increased αS expression and affecting its membrane binding and aggregation in neurons (38). The presence of PI in phospholipid vesicles significantly increases the binding of soluble αS to the membrane and leads to extensive phospholipid bilayer disruption and aggregate formation (39). However, the specific mechanism needs further study.

Our findings support that LDL-C and RC are high risk factors for LBD, and dietary modification of LDL-C and RC levels in addition to medications may have a positive impact on prognostic outcomes. In a recent study, APOE4 carriers with higher dietary cholesterol intake were found to have a poorer lipid profile, which was associated with a higher risk of dementia and cognitive impairment. These associations were not observed in non-APOE4 allele carriers. The findings suggest that unfavorable lipid profile may be an important clinical indicator of dementia risk, especially in individuals with the APOE4 genotype. Dietary modifications to reduce the risk of dementia in the early stages of the disease include reducing the intake of saturated fats, trans fats and cholesterol to achieve healthy lipid levels (32). However, the current evidence does not sufficiently validate the use of omega-3 fatty acid supplements as a treatment for Alzheimer’s disease (40). Moreover, their efficacy in diminishing the occurrence of Alzheimer’s is also not convincingly demonstrated (41). In addition, the composition and structure of cell membrane lipid components can be altered in a targeted therapeutic manner, such as by up- or downregulating the expression of specific lipids, enzymes, or transcription factors, to treat disease, an approach known as membrane lipid therapy (MLT). For example, docosahexaenoic acid (DHA) has been used in research to treat Alzheimer’s disease. By design, 2-hydroxy-DHA (LP226A1, Lipopharma) was tested in a severe Alzheimer’s disease model animals (5XFAD mice). And 4 months of treatment with this synthetic unsaturated fatty acid increased new neuron production and restored cognitive scores on the radial maze test to control values (42). Our study identified lipidome components that are closely associated with the development of LBD and APOE4 allele-carrying LBD. It will help researchers develop targeted precision therapies for LBD in the future.

The advantage of this study is that the LBD GWAS data used is the largest and only sample data set. Although the original data was from multicenter and the participants spanned Europe and the United States, no heterogeneity, pleiotropy, and reverse causality were observed in a series of sensitivity analyses and reverse MR, which ensures the reliability of the results in our research. Similarly, the shortcomings of the study should not be overlooked. First, it only established causality between certain lipids and LBD or the APOE4 allele, without delving into mechanisms which need further basic research. Second, due to the limitations of GWAS data, we were unable to perform detailed subgroup analyses based on sex and age, and new GWAS data containing variables such as sex and age need to be utilized for more personalized subgroup studies in the future. Finally, the GWAS data for the lipidomes used in the study were from the Finnish people. Therefore, it needs to be further verified by large multicenter RCT studies in different ethnicities and regions.

In this TSMR study, our findings provide evidence for a causal relationship between lipids, lipid composition and the risk of LBD and APOE allele-carrying LBD. The results suggest that certain lipids, such as LDL-C, RC, PI, and some PCs, are associated with increased LBD risk, while some subset of PCs may offer protection. In addition, different lipid components also affect the risk of APOE allele-carrying LBD, but their components are completely different with LBD. Our findings pave the way for a better understanding of serum lipids’ impact on LBD and APOE allele-carrying LBD, hope to guide the development of specific treatments. However, further research is needed to clarify the detailed mechanisms of lipids influence on LBD and APOE allele-carrying LBD risk.

All GWAS data are publicly available, the original study has been reviewed by an ethics committee, all participants have signed an informed consent form, and further information about the data can be obtained by contacting the corresponding author.

We want to acknowledge all participants in the original GWAS study. We would also like to acknowledge BioRender.com for drawing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by the following: National Key R&D Program of China (No. 2022YFE0209900, 2021YFC2500600 and 2021YFC2500602); the National Natural Science Foundation of China (No. 81700792, 82360181).

Ethical approval was not required for this study in accordance with the local legislation and institutional requirements because the studies presented used previously published data (GWAS).

QF: Methodology, Resources, Visualization, Writing – original draft. GP: Software, Writing – original draft. QY: Methodology, Visualization, Writing – original draft. ZL: Validation, Investigation, Writing – original draft. TS: Methodology, Writing – original draft. XM: Conceptualization, Writing – original draft. LJ: Methodology, Funding acquisition, Writing – review & editing.

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2024.1456005/full#supplementary-material↗