You may have seen the hub-bub about the recent lean mass hyper responder study and whether or not the state of remarkably elevated lipoproteins in a low insulin environment tracks with accelerated CVD progression. Honestly, my take on that is it does not look favorable, but I received a tangential question about how APOE4 genotype might factor into the LMHR story. It’s a spicy-meatball to unpack, but this is a short stab at the topic:
Some things to consider about apoe4: seems to track with elevated lipoproteins, elevated cholesterol, elevated triglycerides. A possible evolutionary advantage of apoe4 is enhanced inflammatory response which may confer survival advantage in pre-industrial settings, and may be a liability in modern times. Apoe4 also tracks with increased alzheimer's risk.
That's a superficial treatment of things but sets us up to think this through a bit: Ketogenic diets just about universally elevate cholesterol and lipoproteins. This is not universal, but damn near. Magnitude varies. Lean, athletic folks seem to experience the largest magnitude change (which is the LMHR phenotype described in this study). A KD typically means increased sat'd fat, although other variants can be much lower in sat'd fat, but this is likely a factor in all this....a "Mediterranean keto" seems to elevate lipoproteins less than a dairy fat rich approach (butter and cream seem to exert an effect here disproportionate to their fatty acid profile...that's a whole other rabbit track).
So, depending on a number of factors any given individual is likely to see at least some bump in lipoproteins. Some see a massive increase. What does all that mean for the apoe4 individual? I think increased lipoproteins track poorly with CVD. BUT, a KD is known to be anti-inflammtory with is recognized to be at least a factor in CVD, AND when we think about the neuroprotective effects of a KD (pretty well established) it may be that the APOE4 individual is increasing CVD risk, possibly reducing AZD risk. I'd put a pretty big maybe on that, but mechanistically it makes sense.
I think this is a point that often gets missed in all this and is kinda at the root of things like statins and number needed to treat: There is a trade-off to damn near everything.
I'm apoe3/3 and have used a KD for ~25 years to manage gut and autoimmune issues. My lipoproteins are bit elevated. Not anywhere near LMHR, but also not squeaky clean by life insurance actuarial charts. I tinker with things like adding 50-75g of carbs per day to bring down lipoproteins, while using MCT to goose ketone levels. I'm also pretty active which allows for significantly more carbs while still being in a mild state of ketosis. The thing that will kill me will almost certainly be CVD...but given all my other factors, that's also likely a good bit down the road AND if I did not eat this way my life would be miserable now and uncontrolled autoimmune disease is itself a big CVD risk factor. I just see trade-off's in all this but it's also why it's important for the best information available to make our best informed decisions.
Wow, you summarized things that have been rattling around in my brain the last few days.
Most people I know that have adopted a KD have done so because the quality of life is heads and shoulders above anything else they've tried. And since we all die from something, I think it's a reasonable choice to choose overall quality of life.
Also, I'll add that the clients I've worked with that adopt a KD after a SAD don't necessarily consume higher Sat Fat because SAD UPFs generally have so much delicious cheese (cheese-like powdered substance, that is.)
There was a lot of heterogeneity in the LHMR study and apoe status could well have contributed to that. I would also like to have seen status of participants in regard to things like copper status. Given that copper deficiency reliably causes hypercholesterolemia that could be one other factor (I’m a bit of a fan of Morley Robbins and the root cause protocol). Leslie Klevay spent his entire career looking at this with animal models and identified something like 80 commonalities between heart disease in copper deficient animals and these conditions in humans.