A Shared Systemic Metabolic Signature Across the Neurological Disease Spectrum: A Summary-Level Analysis of 274,241...

Background: Neurological diseases share overlapping systemic and molecular features, but the specificity and interpretation of cross-disease metabolomic signatures remain uncertain. Methods: We analyzed summary-level Nightingale NMR metabolomic and genetic data from 274,241 UK Biobank participants across eight neurological endpoints. The disease rankings used here were derived from baseline plasma metabolites predicting future incident disease rather than from contemporaneous diagnostic case-control contrasts. Results: Among 57 priority metabolites with genome-wide significant instruments (2472 SNPs; mean F = 162.4), nine ranked in the top 30 for at least seven of the eight endpoints, defining a shared pre-diagnostic neurological signature confirmed as non-random cross-endpoint convergence by permutation testing (p < 0.0001). Because we did not perform a quantitative non-neurological disease control analysis, this signature should not be interpreted as neurologically specific and may partly reflect systemic morbidity, renal function, body composition, or frailty-related physiology. Forward Mendelian randomization across 45 metabolite-disease pairs found no Bonferroni-significant causal effects; three nominal protective associations are consistent with the number of false-positive findings expected under multiple testing and require replication. Conclusions: These results support a shared systemic, pre-diagnostic metabolic signature across the neurological disease spectrum, while the null MR findings and specificity limitations favor interpretation as a biomarker or prodromal downstream signal rather than a proven causal mechanism. External prospective validation is essential.