AUTHOR=Galle Sara A. , van der Spek Ashley , Drent Madeleine L. , Brugts Michael P. , Scherder Erik J. A. , Janssen Joseph A. M. J. L. , Ikram M. Arfan , van Duijn Cornelia M. 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=11

YEAR=2019

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2019.00020

DOI=10.3389/fnagi.2019.00020

ISSN=1663-4365

ABSTRACT=<p><bold>Background</bold>: 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.</p><p><bold>Objective</bold>: 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).</p><p><bold>Methods</bold>: 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.</p><p><bold>Results</bold>: 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.</p><p><bold>Conclusion</bold>: 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.</p>