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 200...

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Bibliographic Details
Published in:Annals of clinical and translational neurology Vol. 6; no. 9; pp. 1659 - 1670
Main Authors: McGrath, Emer R., Himali, Jayandra J., Levy, Daniel, Conner, Sarah C., DeCarli, Charles S., Pase, Matthew P., Courchesne, Paul, Satizabal, Claudia L., Vasan, Ramachandran S., Beiser, Alexa S., Seshadri, Sudha
Format: Journal Article
Language:English
Published: United States John Wiley & Sons, Inc 01.09.2019
John Wiley and Sons Inc
Wiley
Subjects:
Aged
Alzheimer Disease - blood
Alzheimer Disease - diagnosis
Alzheimer Disease - epidemiology
Alzheimer's disease
Biomarkers
Biomarkers - blood
Cognitive ability
Dementia
Dementia - blood
Dementia - diagnosis
Dementia - epidemiology
Female
Growth factors
Humans
Incidence
Insulin resistance
Insulin-Like Growth Factor Binding Protein 3 - blood
Male
Metabolism
Middle Aged
NMR
Nuclear magnetic resonance
Probability
Prospective Studies
Proteins
Risk
ISSN:2328-9503, 2328-9503
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Summary: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 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.
Bibliography:The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (contract no. N01‐HC‐25195 and no. HHSN268201500001I). This research was supported by an Alzheimer’s Association Clinician Scientist Fellowship (AACSF‐18‐566570), NHLBI grants R01 HL60040 and R01 HL70100, grants from the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033193, U01 AG049505, U01 AG052409), and grants from the National Institute of Neurological Disorders and Stroke (NS017950 and UH2 NS100605). Additional funding for the Systems Approach to Biomarker Research in Cardiovascular Disease (SABRe CVD) initiative was provided by the Division of Intramural Research, NHLBI, and the Population Sciences Branch, NHLBI. MPP is funded by a National Heart Foundation of Australia Future Leader Fellowship (102052). SCC is funded by the National Institute of General Medical Sciences (NIGMS) Interdisciplinary Training Grant for Biostatisticians (T32GM74905‐14). None of the funding entities had any role in the design and conduct of the study; collection, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The views and opinions offered in this manuscript are those of the authors and are not necessarily those of the funding agencies.
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ISSN:2328-9503
2328-9503
DOI:10.1002/acn3.50854