Distinct alterations of adiponectin, fibroblast growth factor 21 (FGF‐21), and insulin‐like growth factor binding protein 2 (IGFBP‐2) link dysmetabolism with cognitive decline across the Alzheimer's disease spectrum

INTRODUCTION: Metabolic disorders are risk factors for Alzheimer's disease (AD), although underlying mechanisms remain unclear. We investigated the relationship between peripheral metabolic markers - adiponectin, fibroblast growth factor 21 (FGF-21), and insulin-like growth factor binding protein 2 (IGFBP-2) - and AD. METHODS: Participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, and cognitively healthy (CH) controls were from the Consortium for the Early Identification of Alzheimer's Disease-Quebec cohort (n = 287). Serum adiponectin, FGF-21, and IGFBP-2 concentrations were measured, compared between groups, and assessed for associations with clinical, cognitive, biochemical, and magnetic resonance imaging (MRI) data. RESULTS: Metabolic dysfunction was linked to lower adiponectin and IGFBP-2, but higher FGF-21. Both FGF-21 and IGFBP-2 increased with age and were inversely associated with cognitive performance. IGFBP-2 was elevated at SCD stage and correlated with plasma tau phosphorylated at threonine 181 and amygdala atrophy. Adiponectin was unrelated to cognition. DISCUSSION: These findings suggest that IGFBP-2 and, to a lesser extent, FGF-21 may serve as early biomarkers of cognitive impairment, reflecting intricate links between peripheral dysmetabolism and AD.