TY - JOUR
T1 - Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults
AU - Wittfeld, Katharina
AU - Raman, Mekala R.
AU - Conner, Sarah C.
AU - Aslam, Asra
AU - Teumer, Alexander
AU - Nauck, Matthias
AU - Hosten, Norbert
AU - Habes, Mohamad
AU - Decarli, Charles
AU - Vasan, Ramachandran S.
AU - Beiser, Alexa S.
AU - Himali, Jayandra J.
AU - Seshadri, Sudha
AU - Grabe, Hans J.
AU - Satizabal, Claudia L.
N1 - Funding Information:
This study was supported by grants from the National Heart, Lung, and Blood Institute contract for the Framingham Heart Study (contract no. N01-HC-25195, no. HHSN268201500001I, and no. 75N92019D00031), the National Institute on Aging (R01 AG054076, R01 AG049607, R01 AG033193, U01 AG049505, U01 AG052409) and the National Institute of Neurological Disorders and Stroke (NS017950 and UH2 NS100605). The measurement of growth factors was funded by R01 HL077477 and R01 AG031287. Dr. Raman received funding from NHLBI (T32HL125232-01A1). Ms. Conner reports funding from the National Institute of General Medical Sciences (NIGMS) Interdisciplinary Training Grant for Biostatisticians (T32GM74905-14). Dr. DeCarli reports funding from P30 AG0101029. Dr. Seshadri reports funding from P30 AG066546. Dr. Satizabal was supported by a New Investigator Research Grant to promote Diversity from the Alzheimer’s Association (AARGD-16-443384).
Funding Information:
SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP-TREND have been supported by a joint grant from Siemens Health-ineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Dr. Habes was supported in part by NIH (grant 1RF1AG054409 and R01 HL127659-04S1) and Allen H. and Selma W. Berkman Charitable Trust (Accelerating Research on Vascular Dementia).
Publisher Copyright:
© 2022-IOS Press. All rights reserved.
PY - 2022
Y1 - 2022
N2 - Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. Methods: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI],-0.05 [-0.09,-0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.
AB - Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. Methods: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI],-0.05 [-0.09,-0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.
KW - Alzheimer's disease endophenotype
KW - C-reactive protein
KW - cohort study
KW - epidemiology
KW - hippocampus
KW - insulin-like growth factor
KW - neuroimaging
KW - white matter hyperintensity
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U2 - 10.3233/JAD-220356
DO - 10.3233/JAD-220356
M3 - Article
C2 - 35599493
AN - SCOPUS:85133723961
SN - 1387-2877
VL - 88
SP - 311
EP - 322
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 1
ER -