Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer’s Disease in Predominantly Middle-Aged Adults

Article type: Research Article

Authors: Wittfeld, Katharina^{a; b; 1} | Raman, Mekala R.^{c; d; 1} | Conner, Sarah C.^e | Aslam, Asra^f | Teumer, Alexander^{g; h; i} | Nauck, Matthias^{h; j} | Hosten, Norbert^k | Habes, Mohamad^{l; m; n} | DeCarli, Charles^o | Vasan, Ramachandran S.^{d; p; q} | Beiser, Alexa S.^{c; d; e} | Himali, Jayandra J.^{c; d; e; l} | Seshadri, Sudha^{c; d; l; 2} | Grabe, Hans J.^{a; b; 2} | Satizabal, Claudia L.^{c; d; l; 2; *}

Affiliations: [a] German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Germany | [b] Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany | [c] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [d] Framingham Heart Study, Framingham, MA, USA | [e] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [f] Long School of Medicine, UT Health San Antonio, San Antonio, TX, USA | [g] Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany | [h] DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany | [i] Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland | [j] Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany | [k] Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany | [l] Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA | [m] Department of Radiology, Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA | [n] Department of Neurology, Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA | [o] Department of Neurology, University of California, Davis School of Medicine, Sacramento, CA, USA | [p] Department of Medicine, Boston University School of Medicine, Boston, MA, USA | [q] Department of Epidemiology, Boston University School of Public Health, Boston MA, USA

Correspondence: [*] Correspondence to: Claudia L Satizabal, PhD, Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, 7703 Floyd Curl Drive, MSC 8070, San Antonio, TX 78229, USA. Tel.: +1 210 450 8417; E-mail: [email protected].

Note: [1] These authors contributed equally to the manuscript.

Note: [2] Equal senior authorship.

Abstract: 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.

Keywords: Alzheimer’s disease endophenotype, C-reactive protein, cohort study, epidemiology, hippocampus, insulin-like growth factor, neuroimaging, white matter hyperintensity

DOI: 10.3233/JAD-220356

Journal: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 311-322, 2022