Large-scale proteome analysis of CSF implicates altered glucose metabolism in Alzheimer's disease

A major hallmark of Alzheimers disease (AD) is the aggregation of proteins ({beta}-amyloid (A) and hyperphosphorylated tau (T)) in the brain, which makes the AD proteome in cerebrospinal fluid (CSF) of particular interest. Here, we conducted a CSF proteome-wide analysis among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), using a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. We identified 61 proteins significantly associated with AT category (P < 5.46 x 10-5; strongest was SMOC1, P = 1.87 x 10-12) and 636 significant protein-biomarker associations (P < 6.07 x 10-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 x 10-25). Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks centered around amyloid and tau measures, neurogranin, and the remaining biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were associated with CSF phosphorylated tau levels in an independent replication cohort of 717 participants (P = 8.65 x 10-56 and P = 1.35 x 10-45). Follow-up interrogation of related CSF metabolite levels in the same samples as the discovery proteomics analysis identified increasing levels of succinylcarnitine with ptau and numerous other CSF biomarkers (P < 0.00056) that were replicated in an independent sample of 363 participants. Together, these results implicate glucose metabolic dysregulation and increased CSF succinylcarnitine levels as amyloid and tau pathology emerge in AD. One Sentence Summary: Combining cerebrospinal fluid proteomics data with neurodegeneration and neuroinflammation biomarkers, genomics, and cerebrospinal fluid metabolomics, we identify and replicate a theme of altered glucose metabolism proteins and the metabolite succinylcarnitine across amyloid and tau progression in Alzheimers disease.