Apoe4 mechanistics and a protocol for the reversal of cognitive decline
Description of a comprehensive therapeutic program to reverse cognitive decline in SCI, MCI and early AD.
Dale spoke eloquently and with authority about his program for prevention and reversal of cognitive decline.
We all know it very well, his findings of the apoe4 molecule binding to cell membrane receptors, interacting with RelA (a pro-inflammatory mediator) and enters the nucleus. Here it binds to 1800 gene promotors and these effects resultin increase in NFkB and decrease in SIRT1. This is a pro-inflammatory state as opposed to a SIRT1 dominant anti-inflammatory state.
This is the ancestral allele. Apoe3 appeared around 220 000 years ago and Apoe2 only 70 to 80 000 years ago. Apoe2, being a dominant inflammatory state, has advantages in a situation of living in the bush, waking barefoot, eating carrion, fighting over resources. Also of note is that E4s tend to be hyperabsorbers of fats. This is hugely advantageous in times of famine as reserves will be higher, however not so good in the context of our present abundance of food.
In today's environment, Dale and his team have identified 36 "holes in the roof " which he uses as a metaphor for detrimental downstream effects resulting in dementia. There are complex interactions involving glucose homeostasis, microtubule disassembley, inflammation, neurotrophins and cell death, synapse dysfunction. He feels amyloid is a protective response to three main stressors-1. inflammation both infectious and sterile (HSV, EBV, CMV, biofilms/ AGE modified molecules) - 2. withdrawal of trophic support (nerve growth factor, estrogen, testosterone, D3 )- and 3. response to toxins (eg mercury, mycotoxins)
He calls these types 1 2 and3. There is also an intermediate group 1.5which he calls glycotoxic. Here AGEs cause inflammation which leadsto insulin resistance thus with IR trophic support is effectively lacking.
He also has shown that in a trophic support environment the amyloid precursor molecule is cleaved into two functional parts. In an antitrophic environment it is cleaved into smaller fragments, one of which is abeta which unfortunately seems to accumulate in a prionic-like manner. The downstream effect is accumulated amyloid, tau and mitochondrial dysfunction.
He then described his program which we all know very well.
My opinion: brilliant as always, clearly at the top of his game and likely the world's top expert in the field of Alzheimers. A privilege to hear him speak.