Abstract INTRODUCTION Establishing links between circulating plasma proteins and neuroimaging measures of pathology is essential for advancing biomarker discovery in age‐related cognitive decline. METHODS Blood plasma proteins were measured using Olink's targeted panels in predominantly mild cognitive impairment participants from cross‐sectional ( N = 287) and longitudinal ( N = 125) cohorts. We assessed associations between 88 neurology‐related and 40 inflammatory‐related proteins with dementia severity and neuroimaging measures from 3T magnetic resonance imaging and global amyloid beta (Aβ) positron emission tomography. RESULTS Several proteins were cross‐sectionally associated with dementia severity, most mediated by white matter integrity. Decreased brevican (BCAN) expression was associated with dementia severity, partially mediated by white matter integrity and Aβ deposition. Lower baseline BCAN levels were longitudinally associated with worse dementia outcomes over 2 years. DISCUSSION These findings highlight the potential of plasma proteins, particularly BCAN, as biomarkers of cognitive decline and neuroimaging pathology, warranting replication and mechanistic follow‐up studies. CLINICAL TRIAL REGISTRATION The BICWALZS is registered in the Korean National Clinical Trial Registry (Clinical Research Information Service; identifier, KCT0003391, Registration date 11/11/2016). Highlights We linked plasma protein levels to dementia severity and neuroimaging measures. White matter integrity and amyloid beta deposition mediated several of these associations. Brevican levels were linked to worse dementia outcomes over 2 years. Findings highlight potential plasma biomarkers for clinical dementia progression.
Schweitzer et al. (Thu,) studied this question.