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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.

Original publication




Journal article


Front Aging Neurosci

Publication Date





Alzheimer’s disease, KIRA assay, apolipoprotein E, dementia, genetic epidemiology, insulin-like growth factor I