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

Author(s): Panyard, DJ; McKetney, J; Deming, YK; Morrow, AR; Ennis, GE; Jonaitis, EM; Van Hulle, CA; Yang, C; Sung, YJ; Ali, M; Kollmorgen, G; Suridjan, I; Bayfield, A; Bendlin, BB; Zetterberg, H; Blennow, K; Cruchaga, C; Carlsson, CM; Johnson, SC; Asthana, S; Coon, JJ; Engelman, CD;
Year: 2023;  
Journal: Alzheimer's & Dementia: The Journal of the Alzheimer's Association;  

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.