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.