Differential/opposite effects of insulin growth factor binding protein in E4/4

[Harrison]

This is an interesting finding: https://www.ncbi.nlm.nih.gov/pubmed/28968233:

Curiously, however, higher IGFBP-2 corresponded to better cognitive performance in the RAVLT Delay, as well as global indices for APOE4 carriers only. These conflicting results may be due to a progression of insulin resistance, where the body is at first able to compensate for insulin resistance by releasing additional IGF to keep up with glucose demands of neuronal cells. Although much of glucose transport in the brain is insulin-independent via GLUT-1 and GLUT-3, insulin is necessary for GLUT-4 actions, which in rats has been detected in the cerebellum, olfactory bulb, and dentate gyrus of the hippocampus [28]. Although further research is necessary to translate these findings to humans, Craft et al. showed that intranasal insulin reduced progression of neuronal hypometabolism in individuals with MCI and AD, suggesting that insulin does play an important role in glucose uptake in the brain [29]. We hypothesize that central insulin resistance progresses to a point where GLUT-4 receptors are unable to respond to insulin and cells are delivered a suboptimal level of glucose. We suggest that the cognitive score results in our study are representative of the early compensatory response, which may in part be related to APOE4 status, while the GM, FDG, and diagnosis results are indicative of a post-compensatory state. In general, having one or more E4 alleles corresponded to higher IGFBP2 predicting better cognitive performance, whereas for non-APOE4s either no association or a detrimental pattern was observed, such as for ADAS-cog. Additionally, previous research has shown that individuals who are APOE4 positive have lower expression of insulin degrading enzyme, thus potentially amplifying the early cognitive benefits of higher IGFBP-2 510 levels [30].

Wish I could post the graph as the effects on cognition are really striking. E4/4 and no E4 are completely opposite, with E4/x being kind of a middle ground. Not sure what it means for strategies (probably nothing), but just goes to show things are different with E4 (ugh, that sounds like a commercial tag line).

[Julie G]

Counterintuitive... understatement. It's worth mentioning that higher IGFBP-2 is associated with MetS and multiple cancers (esp. glioblastoma & lung cancer) Typically a bad player. The only way that this makes sense in my current world view is to grasp at the short term compensatory idea for homozygotes. It would be great to do longitudinal testing (every six months) with the same 4/4 individuals to test this concept. An eventual decline in cognition should be noted. Otherwise, off for ice cream .

[Harrison]

ApoE research is coming fast and furious these days. Here is a mouse paper that suggests apoE4 may directly cause insulin resistance by binding to insulin receptors and then stopping them from being properly recycled:
https://www.ncbi.nlm.nih.gov/pubmed/28957663

Here is a nice AlzForum summary of the paper:http://www.alzforum.org/news/research-n ... de-neurons.

This may explain why IGFBP-2 was upregulated in ApoE4 carriers, and perhaps more importantly, confirms the view of most of us that glycemic control is paramount for apoE4 carriers.

[Gilgamesh]

Wow, amazing study! Thanks!