Background Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder causing motor neuron degeneration, muscle paralysis, and death within 3–5 years, with a rising global prevalence. While thyroid dysfunction is implicated in the pathology of other neurodegenerative diseases, its role in ALS remains unclear due to conflicting reports from observational studies. To address this, we aimed to investigate the causal relationship between thyroid function and ALS using two-sample Mendelian Randomization (MR). Method We performed a two-sample MR study to evaluate the bidirectional causal relationship between thyroid function traits (TSH, FT4, autoimmune hyperthyroidism, autoimmune hypothyroidism) and ALS. We used SNPs from GWAS data (TSH and FT4: n=271,040; autoimmune hyperthyroidism: n=1,828 cases/279,855 controls; autoimmune hypothyroidism: n=40,926 cases/274,069 controls; ALS: n=27,205 cases/110,881 controls). We applied the inverse-variance weighted (IVW) method as the primary analysis, with sensitivity analyses (MR-Egger, weighted median, weighted mode, MR-PRESSO) to assess pleiotropy and heterogeneity. Results We identified a causal effect of autoimmune hyperthyroidism on reducing ALS risk (IVW OR = 0.96; 95% CI: 0.93–0.99; P = 0.03), but no associations for TSH (IVW OR = 0.99; 95% CI: 0.94–1.04; P = 0.71), FT4 (IVW OR = 1.03; 95% CI: 0.96–1.12; P = 0.36), or autoimmune hypothyroidism (IVW OR = 1.01; 95% CI: 0.98–1.05; P = 0.39) with ALS. Bidirectional analysis of genetic liability to ALS showed no causal effect on TSH (IVW OR = 0.98; 95% CI: 0.96–1.01; P = 0.65), FT4 (IVW OR = 0.98; 95% CI: 0.94–1.02; P = 0.46), autoimmune hypothyroidism (IVW OR = 0.93; 95% CI: 0.76–1.13; P = 0.59), or autoimmune hyperthyroidism (IVW OR = 1.01; 95% CI: 0.76–1.33; P = 0.78). Conclusion We found that genetic predisposition to autoimmune hyperthyroidism may reduce ALS risk. Our findings expand the knowledge of its genetic underpinnings and lay a foundation for future research into therapeutic strategies targeting thyroid function to mitigate ALS risk.

Background: Very few case reports have explored a potential link between ankylosing spondylitis (AS), an autoimmune disorder, and amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative condition. We aimed to investigate whether genetic liability to AS causally influences the risk of ALS, and vice versa, using a bidirectional two-sample Mendelian randomization (MR) framework. Methods: We performed a two-sample MR study to evaluate the bidirectional causal relationship between genetic liability to ankylosing spondylitis and ALS risk. We used 6 valid single nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) data (AS: 1462 cases and 164,682 controls; ALS: 27,205 cases and 110,881 controls). We used the inverse-variance weighted (IVW) approach as the primary statistical method for causal estimation, with sensitivity analyses (including MR-Egger, weighted median, weighted mode, Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO), leave-one-out, and single SNP analysis) to assess pleiotropy and heterogeneity. Results: There was no evidence of a causal association between genetic predispositions to ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS) (IVW OR = 1.01; 95% CI: 0.99–1.02; p = 0.10). The results from the weighted median, weighted mode, MR-Egger, and simple mode methods were consistent and nonsignificant. In the reverse analysis, genetic liability to ALS showed no causal effect on AS (IVW OR = 0.88; 95% CI: 0.70–1.12; p = 0.33), with similar null findings across all sensitivity methods. Conclusions: Overall, our bidirectional two-sample MR analyses provided no evidence supporting a causal relationship between AS and ALS.

Background: The global burden of dementia is escalating due to the aging population. While amyloid and tau biomarkers are central to Alzheimer's disease (AD) pathology, their causal roles across dementia subtypes are not fully understood. Objective: This study investigated the causal effects of cerebrospinal fluid (CSF) and plasma amyloid, tau, and hyperphosphorylated tau (p-tau) proteins on dementia [AD, frontotemporal dementia (FTD), and vascular dementia (VaD)] risk. Methods: In this study, we conducted a two-sample Mendelian randomization analysis using genome-wide association study (GWAS) summary statistics. The AD, CSF, and plasma amyloid, tau, and p-tau data were obtained from the GWAS catalog, while those for FTD and VaD were obtained from the FINNGEN database. The inverse variance weighting method, combined with sensitivity analysis, was used to obtain the estimates. Results: CSF p-tau in individuals with abnormal amyloid and APOE ε4 non-carriers was positively associated with AD risk [IVW: OR = 1.07, 95% CI = 1.01–1.13, p = 0.016; OR = 1.08, 95% CI = 1.02–1.14, p = 0.014, respectively]. CSF p-tau was also associated with VaD (IVW: OR = 1.11, 95% CI = 1.03–1.20, p = 0.008). Plasma Aβ ₁₋₄₂ reduced the odds of FTD (IVW: OR = 0.83, 95% CI = 0.70–0.98, p = 0.03), whereas CSF Aβ ₄₂ increased FTD risk (weighted median: OR = 1.58, 95% CI = 1.02–2.44, p = 0.041). Conclusions: The findings support the causal roles of tau and amyloid across dementia subtypes, reinforcing the value of biomarker-driven prevention and therapeutic strategies.