TY - JOUR
T1 - Circulating IGFBP-2
T2 - a novel biomarker for incident dementia
AU - McGrath, Emer R.
AU - Himali, Jayandra J.
AU - Levy, Daniel
AU - Conner, Sarah C.
AU - DeCarli, Charles S.
AU - Pase, Matthew P.
AU - Courchesne, Paul
AU - Satizabal, Claudia L.
AU - Vasan, Ramachandran S.
AU - Beiser, Alexa S.
AU - Seshadri, Sudha
N1 - Funding Information:
Funding Information 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.
Publisher Copyright:
© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
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U2 - 10.1002/acn3.50854
DO - 10.1002/acn3.50854
M3 - Article
C2 - 31373442
AN - SCOPUS:85072705538
SN - 2328-9503
VL - 6
SP - 1659
EP - 1670
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 9
ER -