In conclusion, our current study sheds new light on the association between IGF-I signaling and the neuropathology of dementia, suggesting a threshold effect of IGF-I receptor stimulating activity moderated by ApoE genotype, since only for those with one or more copies of the ApoE-ε4 allele and in the lowest tertile of IGF-I receptor stimulating activity the risk of future dementia is decreased. Here, APOE is linked to dementia.