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

Abstract

AbstractA major hallmark of Alzheimer’s disease (AD) is the aggregation of misfolded proteins (β-amyloid (A) and hyperphosphorylated tau (T)) in the brain. As these proteins can be monitored by cerebrospinal fluid (CSF) measures, the AD proteome in CSF has been of particular interest. Here, we conducted a proteome-wide assessment of the CSF in an AD cohort among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), identifying a diverse set of proteins in the CSF enriched for extracellular and immune system processes. We then interrogated the proteome using the amyloid, tau, and neurodegeneration (ATN) framework of AD and a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. After multiple testing correction, we identified a total of 61 proteins significantly associated with AT group (P < 5.46 × 10-5; strongest was SMOC1, P = 1.87 × 10-12) and 636 significant protein-biomarker associations (P < 6.07 × 10-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 × 10-25) across all measures except for interleukin-6, which had no significantly associated proteins. Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks: one related to amyloid and tau measures, one to CSF neurogranin, and one to the remaining CSF biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were replicated as strongly associated with AD (P = 1.07 × 10-19 and P = 7.43 × 10-14, respectively) in an independent CSF proteomics cohort (n = 717 participants). Comparative performance of the CSF proteome in predicting AT categorization was high (mean AUC range 0.891–0.924 with number of protein predictors ranging from 37-97) relative to other omic predictors from the genome, CSF metabolome, and demographics from the same cohort of individuals. Collectively, these results emphasize the importance of the CSF proteome relative to other omics and implicate glucose metabolic dysregulation as amyloid and tau pathology emerges in AD.