Mike - thanks for starting this very interesting topic. One thing to note is that in addition to diet, various infectious diseases also likely put strong selective pressure on ApoE.mike wrote: ↑Tue Jun 21, 2022 2:56 pmBigInJapanDan wrote: ↑Tue Jun 21, 2022 1:00 pm Very interesting theory regarding tubers unfortunately, my research is focused more on recent developments (last 10kya), so I cannot contribute much to your theory. Although it would be great if you could provide any sources for your theory
Regarding the carb variant, AD is not (at least directly) affecting fitness/survival in the reproductive stages of humans, so AD alone wouldn't have been able to lead to selection of E3 over E4 – even if nowadays we see that it is typically a western diet that leads to the increased risk associated with E4.
The major receptor for ApoE, LDL-R, is highly conserved among animals and insects. Thus, many viruses have used it and other cholesterol receptors) to cross the species barrier and infect human cells. For example: Vesicular stomatitis virus (LDL-R), Rift Valley (LRP-1), alphaviruses like Yellow fever (ApoER), Ebola (NPC1), rhinoviruses (LDL-R), trypanosomes (LDL-R), Hepatitis C (incorporates ApoE into viral particle)... the list goes on and on. Probably many other viruses that we don't know about use ApoE receptors.
ApoE and its receptors were likely under strong selective pressure to prevent pathogens from using them. ApoE binds with higher affinity to the LDL receptor than ApoE2 or ApoE3. ApoE4 may compete with pathogens for the receptor and this in turn block infection. If E4 is bound to LDL-R then virus wouldn't be able to enter the cell. There could be a strong evolutionary advantage to E4 with pathogen burden is high.
Countries around the equator have a high pathogen burden. Infection is common. As humans moved out of Africa and into higher latitudes the pathogen burden lessened (and as you note diets changed). Winters kill many biting insects thus reducing exposure to viruses. In this lower pathogen environment other ApoE alleles, such as ApoE3 may have been favored.