Xingzhi Guo

Osteokines, primarily secreted by bone, have been implicated in brain function and Parkinson's disease (PD) pathogenesis, yet their circulating levels in PD and potential role in the relationship between bone mineral density (BMD) and PD remain unclear. 80 participants (40 PD patients and 40 controls) were enrolled to measure plasma levels of eight osteokines (GPNMB, OPN, SOST, DKK1, RANKL, FGF23, BMP2, and BMP4) and assess their associations with clinical scales. Mendelian randomization (MR), SMR, and colocalization analyses were performed to evaluate causal relationships between osteokines and PD. Restricted cubic spline (RCS) models were applied to explore nonlinear associations between BMD, osteokines, and PD. GPNMB levels were significantly elevated in PD patients and showed a linear association with PD risk. Higher GPNMB levels were associated with worse cognitive performance and clinical severity, while higher SOST levels correlated with milder symptoms. Genetic analyses consistently supported a causal and colocalized relationship between GPNMB and PD. Total coxa BMD and T-score were lower in PD, but not statistically significant. RCS analysis revealed an "n-shaped" association between total coxa T-score and both PD and GPNMB levels. Overall, GPNMB appears causally linked to PD risk and may mediate the bone-brain axis connecting BMD with PD susceptibility.

Background: Elevated levels of ApoB and LDL‐C have been associated with CI ¹ . The LDL‐C/ApoB ratio is a marker of LDL particle size, with smaller, denser LDL (sdLDL) particles being more atherogenic and a risk factor for cardiovascular diseases ² . However, the relationship between LDL‐C/ApoB and CI remains unclear. Method: This study utilized data from the NHANES covering the years 2011 to 2014, including 1,105 participants over 60 years old. To investigate the relationship between LDL‐C/ApoB and CI, the logistic regression analysis was employed. Furthermore, the restricted cubic splines (RCS) were applied to explore potential nonlinear relationships between them. Result: The average age of participants was 68 years (interquartile range [IQR]: 63–74), and 537 (48.6%) participants were male. Logistic regression analysis showed no significant association between ApoB and CI (OR: 1.003, 95% CI: 0.998–1.008, p = 0.215), while a significant association was observed between LDL‐C/ApoB and CI (OR: 1.519, 95% CI: 1.206–1.922, p < 0.001). The results remained consistent after adjusting for gender and age (OR: 1.349, 95% CI: 1.062–1.718, p < 0.05). Further RCS analysis indicated a nonlinear relationship between LDL‐C/ApoB and CI (P _non‐liner < 0.0001), even after adjusting age and gender (P _non‐liner < 0.0001). Conclusion: Our study demonstrates that the LDL‐C/ApoB ratio is a potential risk factor for CI in the elder population. Thus, maintaining an optimal LDL‐C/ApoB ratio might be crucial in preventing CI.

Alzheimer’s disease (AD) and osteoporosis (OP) are prevalent age-related degenerative diseases that often coexist. Echinacoside (ECH) has been extensively studied for its potential to mitigate AD and bone mineral density (BMD) loss. This study aimed to evaluate the simultaneous therapeutic effects of ECH on AD-OP comorbidity using the senescence-accelerated mouse-prone 8 (SAMP8) model, which exhibits both age-related memory deficits and bone metabolism abnormalities. Six-month-old male SAMP8 mice (n = 8–9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice served as normal controls. SAMP8 mice were administered ECH intragastrically (100 mg/kg/day) for 10 weeks, while control groups received saline. Behavioral tests, including the open field test (OFT), novel object recognition test (NORT), and Morris Water Maze (MWM), assessed locomotor ability, emotionality, and cognitive functions. Bone microstructure was evaluated using micro-computed tomography (micro-CT), and pathological changes in the brain were analyzed via Western blotting and immunofluorescence. As compared to SAMR1 mice, SAMP8 mice exhibited significant locomotor activity issues, impaired memory (P < 0.05), glial activation (P < 0.01), reduced trabecular bone number (P = 0.007), and altered trabecular separation (P = 0.040). ECH treatment improved memory function and inhibited glial activation (P < 0.05). Bone-related parameters showed that ECH intervention had a trend of improvement in bone health, but this did not reach statistical significance. The SAMP8 model exhibits key features of both AD and OP, making it a valuable tool for investigating their comorbidity and underlying mechanisms. ECH improves cognitive functions and alleviates bone loss, indicating its potential as a therapeutic candidate for AD-OP comorbidity.

Background: Observational studies indicate a complex relationship between coagulation factors and Alzheimer's disease (AD). However, the current findings are inconsistent, and it remains uncertain whether a causal relationship exists. Objective: This study utilizes a Mendelian randomization analysis to investigate the causal relationships between blood levels of coagulation factors and AD risk. Methods: Eleven coagulation factors with valid instrumental variables available were evaluated. Two independent cohorts of European ancestry with AD genome-wide association study (GWAS) summary statistics were used: UK Biobank (UKB, N = 472,868) and the International Genomics of Alzheimer's Project (IGAP, N = 63,926). We primarily conducted Mendelian randomization (MR) analyses using the Inverse variance weighted (IVW). Meanwhile, the MR-Egger intercept test is used to detect horizontal pleiotropy, the Residual Sum of Squares observed (RSSobs) is used to assess the model's goodness of fit, and the leave-one-out analysis is employed for sensitivity analysis. Results: Using IVW analysis, the UKB database shows positive correlations of Protein C (PC, p = 0.002), Activated Partial Thromboplastin Time (aPTT, p = 0.019), and coagulation factor X (FX, p = 0.032) with AD, and a negative association for coagulation factor XI (FXI, p = 0.021). The IGAP database mirrors these findings for PC and FXI but not for the others. Leave-one-out analysis showed an anomaly after a single single nucleotide polymorphism (SNP) driving, yet the overall results remained stable. Conclusions: This study demonstrates that elevated levels of PC, FX, and aPTT, along with reduced levels of FXI, are causally associated with an increased risk of AD. These findings might pave the way for the diagnosis and treatment of AD.

INTRODUCTION: Observational studies have revealed a close relationship between reduced bone mineral density (BMD) and Alzheimer's disease (AD) risk. The receptor activator of nuclear factor kappa‐B ligand (RANKL) and osteoprotegerin (OPG) system, pivotal in regulating bone metabolism, has been implicated in brain function, but the causal impact on AD risk remains unclear. METHODS: We employed bi‐directional Mendelian randomization (MR) and multivariable MR (MVMR) approaches to elucidate the effect of blood soluble RANKL (sRANKL) and OPG levels on AD, assessing whether this influence was independent of BMD and inflammation. Three distinct AD genome‐wide association study (GWAS) data sets from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen were utilized. Summary‐level data on blood sRANKL and OPG were sourced from deCODE Genetics. RESULTS: Genetically predicted per standard deviation (SD) increase in blood sRANKL levels was significantly associated with a reduced risk of AD across all three AD GWAS data sets (IGAP: odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.72–0.94, p = 0.004; UKB: OR = 0.85, 95% CI = 0.78–0.91, p < 0.001; FinnGen: OR = 0.83, 95% CI = 0.73–0.94, p = 0.004). No significant causal relationship was observed between OPG levels and AD. In addition, there was no causal impact of AD on the blood levels of sRANKL and OPG. MVMR results showed that the inverse association between sRANKL and AD risk persisted after adjusting for BMD and interleukin‐1α and chemoattractant protein‐1. DISCUSSION: Our study provides evidence that elevated sRANKL levels are causally linked to a reduced risk of AD, independent of BMD and inflammation. These findings enhance our understanding of the complex interactions between bone metabolism and AD. Highlights: Blood soluble receptor activator of nuclear factor kappa‐B ligand (sRANKL) levels are linked to a reduced risk of Alzheimer's disease (AD). The association between sRANKL levels and AD is independent of bone mineral density (BMD) and inflammation. No causal link exists between blood osteoprotegerin levels and AD. AD does not affect blood levels of sRANKL or osteoprotegerin.

Background: Vertigo is a highly prevalent symptom with wide‐ranging causes and adverse consequences. While common risk factors for vertigo have been identified, their causal relationship with vertigo remains not fully known. Thus, identifying the modifiable factors causally related to vertigo is crucial for preventing vertigo. Methods: A comprehensive Mendelian randomization study was employed to investigate the causal effects of vertigo among more than 40 genetically predicted modifiable risk factors, categorized into lifestyle traits, blood parameters, and metabolic comorbidities. This study used two different vertigo summary statistics from the deCODE and FinnGen consortia. Estimates were calculated using the inverse‐variance weighted method and validated through alternative approaches. Results: The results indicated that genetically predicted higher educational level was significantly associated with a decreased risk of vertigo (deCODE: odds ratio (OR) = 0.757, 95% CI = 0.697–0.822, p _{FDR[false discover rate]} < 0.001; FinnGen: OR = 0.796, 95 % CI = 0.703–0.901, p _FDR = 0.007), while genetically predicted longer television watching was significantly associated with an increased risk of vertigo (deCODE: OR = 1.193, 95 % CI = 1.076–1.323, p _FDR = 0.011; FinnGen: OR = 1.269, 95 % CI = 1.085–1.483, p _FDR = 0.030). Additionally, genetically predicted elevated levels of alanine transaminase (ALT) were positively associated with the risk of vertigo. Genetically predicted increased physical activity was suggestively related to a reduced risk of vertigo, while higher triglyceride, body mass index (BMI), and diastolic blood pressure (DBP) were suggestively associated with an increased risk of vertigo ( p _raw < 0.05). Conclusions: Our findings indicate that genetically predicted increased educational levels and physical activity were associated with a decreased risk of vertigo, while higher levels of ALT and triglycerides, television watching time, BMI, and DBP were positively associated with the risk of vertigo. Thus, modifying these factors would decrease the risk of vertigo.

Background: Alzheimer's disease (AD) is the most common form of dementia, characterized by cognitive impairment and memory loss. Previous studies have demonstrated that plasminogen, a key molecule in the fibrinolytic system, is implicated in the pathophysiology of AD. However, it is yet unknown whether the relationship between blood plasminogen and AD is causal.Methods: Leveraging instrumental variables (IV) from genome‐wide association studies (GWAS), we performed a two‐sample Mendelian randomization (MR) analysis to investigate the causal relationship between plasminogen levels and AD risk. Summary‐level data on blood plasminogen levels was from a GWAS on human blood plasma proteome, and summary statistics on AD were from the International Genomics of Alzheimer's Project (IGAP, N=63,926). Inverse variance weighted (IVW) was used as the primary approach to calculate the estimate, which was further validated using the following sensitivity analyses, including MR‐Egger, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR‐PRESSO), weighted median, simple mode, and weighted mode methods. Additionally, tests for pleiotropy and heterogeneity were conducted to further assess the stability of the MR estimates.Results: Using the IVW approach, our findings revealed a significant association between higher genetically determined plasminogen levels and an increased risk of AD (odds ratio [OR] = 1.10, 95%CI = 1.04‐1.16, P =0.008), which was further confirmed in sensitivity analyses (Figure 1A). The leave‐one‐out analysis plot revealed that the causal estimate between plasminogen levels and AD was not driven by any single instrumental variable (Figure 1B). The findings from the MR‐Egger intercept test and Cochran's Q test revealed an absence of significant directional horizontal pleiotropy and heterogeneity, suggesting a high level of stability in the current MR study.Conclusions: According to our research, there is a direct causal link between increased circulating plasminogen levels and a higher risk of AD. Further studies are warranted to evaluate the underlying mechanism of our findings.

Observational studies have indicated that breakfast skipping and gut microbiome dysbiosis are associated with a higher risk of major depressive disorder (MDD). However, it remains unknown whether the alteration of gut microbes is implicated in the associations between breakfast skipping and MDD. Leveraging genome-wide association studies (GWAS) on breakfast skipping, gut microbes, and MDD, we conducted a two-step Mendelian randomization (MR) study to determine the causal associations between breakfast skipping (N = 193,860) and MDD (N = 1,815,091), and evaluate the role of gut microbes (N = 18,340). Genetic variants with a P-value less than 5E-08 were selected as instrumental variables (IVs). The false discovery rate (FDR) method was employed to correct the P-values for multiple tests in gut microbes. Breakfast skipping was associated with an increased risk of MDD (odds ratio [OR] = 1.36, 95%CI = 1.12–1.65, P = 0.002), but no effect of MDD on breakfast skipping was observed (β per doubling odds of MDD =-0.001, 95%CI=-0.024 to 0.023, P = 0.957). After adjusting for multiple comparisons, the MR analysis provided little evidence for an association between breakfast skipping and the abundance of any gut microbes (PFDR>0.05). Among the 21 gut microbes with IVs available, only the abundance of Class Actinobacteria was causally associated with a reduced risk of MDD (OR = 0.85, 95%CI = 0.75–0.97, PFDR=0.015). Our findings demonstrated that breakfast skipping was associated with an increased risk of MDD, but provided little evidence supporting the role of the abundance of gut microbes in it. Further efforts with a large sample size are warranted to clarify the findings.