Background Triggering receptor expressed on myeloid cell 1 (Trem1) is an important regulator of cellular inflammatory responses. Neuroinflammation is a common thread across various neurological diseases. Soluble Trem1 (sTrem1) in plasma is associated with the development of central nervous system disorders. However, the extent of any causative effects of plasma sTrem1 on the risk of these disorders is still unclear. Method Genetic variants for plasma sTrem1 levels were selected as instrumental variables. Summary-level statistics of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, cerebrovascular diseases, and migraine were collected from genome-wide association studies (GWASs). Whether plasma sTrem1 was causally associated with neurological disorders was assessed using a two-sample Mendelian randomization (MR) analysis, with false discovery rate (FDR)-adjusted methods applied. Results We inferred suggestive association of higher plasma sTrem1 with the risk of AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064, 95% CI 1.012–1.119, P = 0.014, PFDR = 0.056). Moreover, there was significant association between plasma sTrem1 level and the risk of epilepsy (OR per one SD increase = 1.044, 95% CI 1.016–1.072, P = 0.002, PFDR = 0.032), with a modest statistical power of 41%. Null associations were found for plasma sTrem1 with other neurological diseases and their subtypes. Conclusions Taken together, this study indicates suggestive association between plasma sTrem1 and AD. Moreover, higher plasma sTrem1 was associated with the increased risk of epilepsy. The findings support the hypothesis that sTrem1 may be a vital element on the causal pathway to AD and epilepsy.

Background: Extensive studies put forward the association between Alzheimer’s disease (AD) and psychiatric disorders; however, it remains unclear whether these associations are causal. Objective: We aimed to assess the potential causal relationship between major psychiatric disorders and AD. Methods: A bidirectional two-sample Mendelian randomization (MR) was applied to evaluate potential causality between five psychiatric disorders and AD by selecting the single-nucleotide polymorphisms from the genome-wide association studies as instrumental variables. Inverse-variance weighted (IVW) method was used as the main analyzing approach to estimate possible causal effects, alternative methods including MR-Egger, the MR pleiotropy residual sum and outlier, and leave-one-out analysis method were implemented as sensitivity analyzing approaches to ensure the robustness of results. Results: All forward and reverse MR analyses consistently suggested absent causal relations between psychiatric disorders and AD risk [forward IVW: ORADHD, 1.030, 95% CI, 0.908–1.168, p = 0.674; ORanxiety disorders, 0.904, 95% CI, 0.722–1.131, p = 0.377; ORASD, 0.973, 95% CI, 0.746–1.272, p = 0.846; ORBIP, 1.033, 95% CI, 0.925–1.153, p = 0.564; and ORschizophrenia, 1.039, 95% CI, 0.986–1.095, p = 0.156; reverse IVW: ORADHD, 0.993, 95% CI, 0.954–1.034, p = 0.746; ORanxiety disorders, 1.000, 95% CI, 0.999–1.000, p = 0.898; ORASD, 1.001, 95% CI, 0.962–1.042, p = 0.949; ORBIP, 0.997, 95% CI, 0.966–1.028, p = 0.831; and ORschizophrenia, 1.013, 95% CI, 0.978–1.051, p = 0.466]. Conclusion: There is no significant evidence supporting the causal association between the five major psychiatric disorders and AD.

Background Previous studies have found a correlation between coronavirus disease 2019 (COVID-19) and changes in brain structure and cognitive function, but it remains unclear whether COVID-19 causes brain structural changes and which specific brain regions are affected. Herein, we conducted a Mendelian randomization (MR) study to investigate this causal relationship and to identify specific brain regions vulnerable to COVID-19. Methods Genome-wide association study (GWAS) data for COVID-19 phenotypes (28,900 COVID-19 cases and 3,251,161 controls) were selected as exposures, and GWAS data for brain structural traits (cortical thickness and surface area from 51,665 participants and volume of subcortical structures from 30,717 participants) were selected as outcomes. Inverse-variance weighted method was used as the main estimate method. The weighted median, MR-Egger, MR-PRESSO global test, and Cochran’s Q statistic were used to detect heterogeneity and pleiotropy. Results The genetically predicted COVID-19 infection phenotype was nominally associated with reduced cortical thickness in the caudal middle frontal gyrus (β = − 0.0044, p = 0.0412). The hospitalized COVID-19 phenotype was nominally associated with reduced cortical thickness in the lateral orbitofrontal gyrus (β = − 0.0049, p = 0.0328) and rostral middle frontal gyrus (β = − 0.0022, p = 0.0032) as well as with reduced cortical surface area of the middle temporal gyrus (β = − 10.8855, p = 0.0266). These causal relationships were also identified in the severe COVID-19 phenotype. Additionally, the severe COVID-19 phenotype was nominally associated with reduced cortical thickness in the cuneus (β = − 0.0024, p = 0.0168); reduced cortical surface area of the pericalcarine (β = − 2.6628, p = 0.0492), superior parietal gyrus (β = − 5.6310, p = 0.0408), and parahippocampal gyrus (β = − 0.1473, p = 0.0297); and reduced volume in the hippocampus (β = − 15.9130, p = 0.0024). Conclusions Our study indicates a suggestively significant association between genetic predisposition to COVID-19 and atrophy in specific functional regions of the human brain. Patients with COVID-19 and cognitive impairment should be actively managed to alleviate neurocognitive symptoms and minimize long-term effects.

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Background: Neurological disorders, such as Alzheimer’s disease (AD), comprise a major cause of health-related disabilities in human. However, biomarkers towards pathogenesis or novel targets are still limited. Objective: To identify the causality between plasma proteins and the risk of AD and other eight common neurological diseases using a Mendelian randomization (MR) study. Methods: Exposure data were obtained from a genome-wide association study (GWAS) of 2,994 plasma proteins in 3,301 healthy adults, and outcome datasets included GWAS summary statistics of nine neurological disorders. Inverse variance-weighted MR method as the primary analysis was used to estimate causal effects. Results: Higher genetically proxied plasma myeloid cell surface antigen CD33 level was found to be associated with increased risk of AD (odds ratio [OR] 1.079, 95% confidence interval [CI] 1.047–1.112, p = 8.39×10 - 7). We also discovered the causality between genetically proxied elevated prolactin and higher risk of epilepsy (OR = 1.068, 95% CI = 1.034–1.102; p = 5.46×10 - 5). Negative associations were identified between cyclin-dependent kinase 8 and ischemic stroke (OR = 0.927, 95% CI = 0.896–0.959, p = 9.32×10 - 6), between neuralized E3 ubiquitin-protein ligase 1 and migraine (OR = 0.914, 95% CI = 0.878–0.952, p = 1.48×10 - 5), and between Fc receptor-like protein 4 and multiple sclerosis (MS) (OR = 0.929, 95% CI = 0.897–0.963, p = 4.27×10 - 5). Conclusion: The findings identified MR-level protein-disease associations for AD, epilepsy, ischemic stroke, migraine, and MS.