LC‐MS/MS proteomics identifies plasma proteins related to cognition over 9‐year follow‐up

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INTRODUCTION: This project identified plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 9-year period. METHODS: Vanderbilt Memory and Aging Project participants (n = 336, 73 ± 7 years, 59% male, 87% non-Hispanic White, 10% Black/African American) underwent blood draw for baseline plasma protein abundance using mass spectrometry analysis of tandem mass tag (TMT)-labeled peptides and serial neuropsychological assessment (follow-up = 6.1 ± 2.3 years). Linear mixed-effects regressions related protein levels to neuropsychological outcomes in fully adjusted models. False discovery rate correction was applied. RESULTS: Initial proteomics analyses yielded 3764 unique protein identifications across 23 16-plex TMT batches, and 686 proteins passed quality control. Proteins were identified predicting longitudinal decline in language (EGFR, RTN4RL2), information processing speed (EGFR, NOMO2, CLEC3B), executive function (A1BG), and visuospatial skills (RTN4RL2, GALNT1, SERPINA4, SERPINA5, C8A, ALDOB), but not episodic memory. DISCUSSION: Large-scale proteomics analyses identified 10 plasma proteins that predicted subsequent cognitive decline over a 9-year follow-up in multiple cognitive domains. HIGHLIGHTS: There were 3764 unique protein identifications across 23 16-plex TMT batches. Rigorous quality control yielded 686 proteins used as predictors in analyses. Identified proteins related to all domains assessed, except for episodic memory. Many proteins identified were differentially expressed in MCI.

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