Assessing the Biological Mechanisms Linking Smoking Behavior and Cognitive Function: A Mediation Analysis of Untargeted Metabolomics.

(1) Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which have both been linked to the development of Alzheimer's disease and related dementias (ADRD). This study identified potential mechanisms of the smoking-cognitive function relationship using metabolomics data from the longitudinal Wisconsin Registry for Alzheimer's Prevention (WRAP). (2) 1266 WRAP participants were included to assess the association between smoking status and four cognitive composite scores. Next, untargeted metabolomic data were used to assess the relationships between smoking and metabolites. Metabolites significantly associated with smoking were then tested for association with cognitive composite scores. Total effect models and mediation models were used to explore the role of metabolites in smoking-cognitive function pathways. (3) Plasma N-acetylneuraminate was associated with smoking status Preclinical Alzheimer Cognitive Composite 3 (PACC3) and Immediate Learning (IMM). N-acetylneuraminate mediated 12% of the smoking-PACC3 relationship and 13% of the smoking-IMM relationship. (4) These findings provide links between previous studies that can enhance our understanding of potential biological pathways between smoking and cognitive function.

Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease.

INTRODUCTION: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTS: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10-5 ) and 636 significant protein-biomarker associations (P < 6.07 × 10-6 ). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.