Revisiting the Role of Insulin-Like Growth Factor-I Receptor Stimulating Activity and the Apolipoprotein E in Alzheimer’s Disease

Frontiers in Aging Neuroscience

Erik J. A. Scherder¹  Ashley van der Spek³  Sara A. Galle³  Joseph A. M. J. L. Janssen⁴  Michael P. Brugts⁵  M. Arfan Ikram⁷  Cornelia M. van Duijn⁸  Madeleine L. Drent⁹ 

[1] Department of Clinical, Neuro- and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands;Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands;Department of Genetic Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands;Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands;Department of Internal Medicine, Ikazia Ziekenhuis, Rotterdam, Netherlands;Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands;Department of Radiology, Erasmus Medical Center, Rotterdam, Netherlands;Nuffield Department of Population Health, Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom;Section of Endocrinology, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, Netherlands;

关键词: Alzheimer’s disease;    dementia;    genetic epidemiology;    insulin-like growth factor I;    KIRA assay;    apolipoprotein E;   

DOI  :  10.3389/fnagi.2019.00020

来源: DOAJ

【 摘 要 】

Background: Alterations in insulin-like growth factor I (IGF-I) signaling have been associated with dementia and Alzheimer’s disease (AD). Studies on the association between IGF-I levels and dementia risk have been inconclusive. We reported earlier that higher levels of IGF-I receptor stimulating activity are associated with a higher prevalence and incidence of dementia.Objective: In the present study, we test the robustness of the association between IGF-I receptor stimulating activity and dementia by extending the follow-up period to 16 years and investigate possible effect modification by apolipoprotein E (ApoE).Methods: At baseline, circulating IGF-I receptor stimulating activity was determined by the IGF-I kinase receptor activation (KIRA) assay in 1,014 elderly from the Rotterdam Study. Dementia was assessed from baseline (1997–1999) to follow-up in January 2015. Associations of IGF-I receptor stimulating activity and incident dementia were assessed with Cox proportional hazards models.Results: During 10,752 person-years of follow-up, 174 people developed dementia. In the extended follow-up we no longer observed a dose-response relationship between IGF-I receptor stimulating activity and risk of dementia [adjusted odds ratio 1.11; 95% confidence interval (CI) 0.97–1.28]. Interestingly, we found evidence of an interaction between ApoE-ε4 and tertiles of IGF-I receptor stimulating activity. IGF-I receptor stimulating activity in the median and top tertiles was related to increased dementia incidence in hetero- and homozygotes of the ApoE-ε4 allele, but did not show any association with dementia risk in people without the ApoE-ε4 allele (adjusted odds ratio medium vs. low IGF-I receptor stimulating activity in ApoE-ε4 carriers: 1.45; 95% CI 1.00–2.12). These findings suggest a threshold effect in ApoE-ε4 carriers. In line with the hypothesis that downregulation of IGF-I signaling is associated with increased dementia risk, ApoE-ε4 homozygotes without prevalent dementia displayed lower levels of IGF-I receptor stimulating activity than heterozygotes and non-carriers.Conclusion: The findings shed new light on the association between IGF-I signaling and the neuropathology of dementia and ask for replication in other cohorts, using measures of IGF-I receptor stimulating activity rather than total serum levels as putative markers of dementia risk.

【 授权许可】

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