Post‐translational modifications linked to preclinical Alzheimer's disease–related pathological and cognitive changes

Abstract INTRODUCTION In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS We constructed a protein co‐expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically‐relevant outcomes. RESULTS We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p‐tau 181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = −2.00, p = 0.005, M7: β = −2.39, p < 0.001). DISCUSSION In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post‐translational modifications for early cognitive and pathological changes.