Plasma proteomic characterization of motoric cognitive risk and mild cognitive impairment

INTRODUCTION: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by mobility and cognitive dysfunction. This study conducted a proteome-wide study of MCR and compared the proteomic signatures of MCR to that of mild cognitive impairment (MCI). METHODS: Participants were classified as MCR using a memory questionnaire and 4-meter walk. We measured 4877 plasma proteins collected during late-life and midlife. Multivariable logistic regression related each protein to late-life MCR/MCI. MCR-associated proteins were replicated internally at midlife and in an external cohort. RESULTS: Proteome-wide analysis (n = 4076) identified 25 MCR-associated proteins. Eight of these proteins remained associated with late-life MCR when measured during midlife. Two proteins (SVEP1 and TAGLN) were externally replicated. Compared to MCI, MCR had a distinct and much stronger proteomic signature enriched for cardiometabolic and immune pathways. DISCUSSION: Our findings highlight the divergent biology underlying two pre-dementia syndromes. Metabolic and immune dysfunction may be a primary driver of MCR. Highlights: MCR is defined by concurrent cognitive and gait dysfunction. MCR protein biomarkers have key roles in cardiometabolic and vascular function. MCR biomarkers are also associated with cerebrovascular disease and dementia. MCR and MCI demonstrate overlapping but divergent proteomic signatures.