Circulating insulin-like growth factors and Alzheimer disease

Abstract

Objective To examine whether genetically predicted variation in circulating insulin-like growth factor 1 (IGF1) or its binding protein, IGFBP3, are associated with risk of Alzheimer disease (AD), using a mendelian randomization study design. MethodsWe first examined disease risk by genotypes of 9 insulin-like growth factor (IGF)-related single nucleotide polymorphisms (SNPs) using published summary genome-wide association statistics from the International Genomics of Alzheimer's Project (IGAP; n = 17,008 cases; 37,154 controls). We then assessed whether any SNP-disease results replicated in an independent sample derived from the Swedish Twin Registry (n = 984 cases; 10,304 controls). Results Meta-analyses of SNP-AD results did not suggest that variation in IGF1, IGFBP3, or the molar ratio of these affect AD risk. Only one SNP appeared to affect AD risk in IGAP data. This variant is located in the gene FOXO3, implicated in human longevity. In a meta-analysis of both IGAP and secondary data, the odds ratio of AD per FOXO3 risk allele was 1.04 (95% confidence interval 1.01-1.08; p = 0.008). ConclusionsThese findings suggest that circulating IGF1 and IGFBP3 are not important determinants of AD risk. FOXO3 function may influence AD development via pathways that are independent of IGF signaling (i.e., pleiotropic actions).

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

“…Although, the majority of studies report a contribution of alterations in IGF-I signaling to the prediction of dementia risk independent of apolipoprotein E (ApoE) genotype (Vargas et al, 2011; Talbot et al, 2012; van Exel et al, 2014; Lane et al, 2017), Deelen et al (2011) reported an association between the ApoE-ε4 allele and lowered total serum IGF-I levels in middle-aged women. However, a recent Mendelian randomization study by Williams et al (2018) did not provide any evidence for an association between genetically predicted variation in total IGF-I or its binding protein IGFBP-3 and risk of AD. These findings decrease the probability that total serum IGF-I is the relevant determinant of AD and dementia.…”

Body Shape and Alzheimer’s Disease: A Mendelian Randomization Analysis

“…The evidence from conventional epidemiological studies regarding the effects of peripheral insulin and IGF-1 levels on the risk of AD has been weak and conflicting. Experimental findings showed that altered peripheral blood levels of insulin or IGF-1 were irrelevant to the normal functionality of the CNS, but insulin or IGF-1 locally produced in the CNS played a more important role in regulating CNS neuronal functions, corresponding with the consistent result of a recent two-sample MR analysis (Steen et al, 2005; Williams et al, 2018).…”

Amyloidogenesis and Neurotrophic Dysfunction in Alzheimer’s Disease: Do They have a Common Regulating Pathway?

“…(4) Evolutionarily conserved cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor family (MANF). Besides the “classical” neurotrophic factors, there are growth factors with neurotrophic effects and newly classified NTFs, such as vascular endothelial growth factor (VEGF) and neurotrophic factor-α1 (NF-α1, also known as carboxypeptidase E or CPE), that have also been linked to AD [ 32 , 33 ]. The NTFs and growth factors which have altered expressions or mutations in AD patients are shown in Table 1 .…”