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.