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.