Circulating IGFBP‐2: a novel biomarker for incident dementia

Abstract

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.

Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer’s Disease

“…In our MR analysis, VDBP did not demonstrate evidence of causality, however, our sample is smaller than Larsson et al and may have lacked statistical power. IGFBP2 has been shown to restrict the neuroprotective effects of insulin growth factors [65] and increased levels have been associated with higher AD risk and lower cognitive performance [66]. In our MR analysis, IGFBP2 did not demonstrate evidence of causality.…”

Circulating ceramide ratios and risk of vascular brain aging and dementia

“…MRI imaging was performed using a Siemens Avanto 1.5 Tesla machine. More detailed methods on MRI brain measures have previously been published . In brief, TBV was defined as supratentorial brain volume as a percentage of the intracranial volume, determined from coronal sections.…”

“…More detailed methods on MRI brain measures have previously been published. 23 In brief, TBV was defined as supratentorial brain volume as a percentage of the intracranial volume, determined from coronal sections. White matter hyperintensity volume (WMHV) was performed on a combination of FLAIR and 3D T1 images using a modified Bayesian probability structure based on a previously published method of histogram fitting.…”

Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer—Its Comparative Expression, Processing and Signaling in Mammalian CNS

“…But IGFs in blood are mostly confined to ternary protein complexes formed with IGFBP3/5 and ALS [37,118] Some recently published data indicate that IGFBPs may participate in both normal and pathological function of the CNS. For example, IGFBP2 is associated with biomarkers of AD [131], and elevated concentration of circulating IGFBP2 was linked with an increased risk of both all-cause dementia and AD [132].…”