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

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-tau181 (M4: beta = 2.44, p < 0.001, M7: beta = 2.57, p < 0.001) and executive function performance (M4: beta = -2.00, p = 0.005, M7: beta = -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.