Circulating IGFBP‐2: a novel biomarker for incident dementia

OBJECTIVE: To determine the association between plasma insulin-like growth factor binding protein 2 (IGFBP-2) and cognitive outcomes. METHODS: We measured plasma IGFBP-2 levels in 1596 (53% women, mean age 68.7 [SD 5.7] years) dementia-free Framingham Offspring cohort participants between 1998 and 2001. Multivariable Cox proportional hazards models related plasma IGFBP-2 to subsequent risk of incident dementia and Alzheimer's disease. MRI brain measures and cognitive performance were included as secondary outcomes. RESULTS: During a median follow-up of 11.8 (Q1, Q3: 7.1, 13.3) years, 131 participants developed incident dementia, of whom 98 were diagnosed with Alzheimer's disease. The highest tertile of IGFBP-2, compared to the lowest tertile, was associated with an increased risk of incident all-cause dementia (hazard ratio [HR] 2.89, 95% CI 1.63-5.13) and Alzheimer's disease (HR 3.63, 95% CI 1.76-7.50) in multivariable analysis. Higher circulating IGFBP2 levels were also cross-sectionally associated with poorer performance on tests of abstract reasoning but not with MRI-based outcomes. After adding plasma IGFBP-2 levels to a conventional dementia prediction model, 32% of individuals with dementia were correctly assigned a higher predicted risk, while 8% of individuals without dementia were correctly assigned a lower predicted risk (overall net reclassification improvement index, 0.40, 95% CI 0.22-0.59). INTERPRETATION: Elevated circulating IGFBP-2 levels were associated with an increased risk of both all-cause dementia and Alzheimer's disease. Addition of IGFBP2 plasma levels to a model of traditional risk factors significantly improved dementia risk classification. Manipulation of insulin-like growth factor signaling via IGFBP-2 may be a promising therapeutic target for dementia.