E2/E4 have MUCH lower risk and much higher apoe levels than E3/E4, so is it the E4 allele that's REALLY causative?
I beg to differ re e2/e4 vs. e3/e4 risk. The ADDF table you attached, what is the study reference?
In the Rasmussen Danish large cohort study, IF you assume the population had similar low E4 levels (why not based on the Reiman & Caselli study and E4 turnover dynamics), then the key differential between the risk level was ALL about the level of non-E4 apoe per dose. That is, E2's had MUCH higher apoe2 > apoe3 > apoe4. This is hugely compelling data re apoe plasma level being a more significant driver of risk.
Re your comment "That being said, if higher peripheral levels help 3/4 carriers and even 4/4 carriers, this is another easy biomarker we can track and tweak." What do you mean by tweak? Are you referring to a way to somehow express /up-regulate your genes to produce MORE non E4 apoe? The answer to that could be the cure to AD? Where do I sign up!
Total apoE levels were positively associated with total plasma cholesterol levels (Spearman’s ρ = 0.6552, p = 0.0005) and this association was driven by the apoE3 isoform levels (Spearman’s ρ = 0.6744, p = 0.0003). Total plasma apoE levels were also positively related to plasma LDL cholesterol levels (Spearman’s ρ = 0.4319, p = 0.0351), which is similar to the link between apoE and total cholesterol driven by apoE3 levels (Spearman’s ρ = 0.4806, p = 0.0174). We found no statistically significant associations between apoE4 isoform levels and any of the plasma lipids.
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