Some fascinating new research out of Stockholm University is looking at something we don’t normally associate with Alzheimer’s disease: the liver.
The researchers are investigating whether APOE4 produced in the liver may contribute to Alzheimer’s risk through its effects on metabolism, inflammation and the vascular system - even though liver-produced APOE itself does not cross the blood-brain barrier (BBB).
Why did this immediately catch my attention?
Because it brought me right back to one of the reasons Dr. Alan Green prescribed rapamycin to me in 2018.
As I explained in a previous post, Dr. Green was very interested in the APOE4 → Cyclophilin A (CypA) → blood-brain barrier pathway.
Research has shown that APOE4 can activate an inflammatory pathway in the cells surrounding our tiny brain blood vessels:
APOE4 → ↑ Cyclophilin A → NF-κB → MMP-9 → weakening of the blood-brain barrier.
And this isn’t just theoretical. Researchers have found evidence of BBB breakdown in cognitively normal APOE4 carriers, particularly in brain regions important for memory. Importantly, that vascular damage can occur independently of amyloid and tau.
So where does rapamycin come in?
In APOE4 mice, rapamycin has been shown to normalize vascular Cyclophilin A signaling, restore blood-brain barrier integrity, improve cerebral blood flow and improve brain glucose metabolism.
That research was one of the things that fascinated Dr. Green and why he insisted that every APOE4 carrier at mid-life (women after menopause) should be proactively protecting the blood brain barrier with once weekly rapamycin.
Now Sweden’s researchers are asking whether some of the signals driving APOE4-related brain vulnerability may actually originate outside the brain - in the liver and systemic circulation.
They are even planning to study approximately 1,500 liver-transplant recipients, creating a remarkable natural experiment: the recipient keeps his or her own APOE genotype in the brain while receiving a liver that may have a different APOE genotype.
Just imagine what we could learn from that!
The Swedish research doesn’t yet show that the liver acts through Cyclophilin A, nor does it prove that rapamycin prevents Alzheimer’s disease in humans.
But the pieces certainly make for an intriguing hypothesis:
APOE4 systemic effects → vascular inflammation → CypA activation → BBB damage → increased brain vulnerability
And potentially:
Rapamycin → mTOR inhibition / reduced vascular inflammatory signaling → better BBB integrity
Nearly eight years after Dr. Green first explained his theory to me, I’m fascinated to see Alzheimer’s research increasingly looking beyond the brain itself. Next month marks 2 years since Dr. Green left this realm…and it would be so exciting to see his theory validated.
We are living in very exciting times. Research is finally closing in on the contributing factors driving cognitive decline. I truly believe we are on the cusp of knowing how to mitigate APOE4 - and I won’t be surprised if APOE4’s deleterious mechanism is uncovered in this decade yet!
So, the whole idea of liver produced apoe4 having a hard time binding to LRP1, hence leaving cyclophylin A free to cause damage to the bbb is purely theoretical and correlative. It is based on a mouse model and has yet to be reproduced in humans. There are so many lifestyle and dietary factors which can cause cyclophylin A to be upregulated and released into circulation, hence the correlation.
Rapamycin is one of those compounds that may be very useful for those who have issues with high blood sugar and cognitive damage, to help decrease the activation of mTORC1 and increase autophagy, but that is about all the benefit I can see in it. If the body is relatively metabolically healthy, I would not risk the negative effects of rapamycin on that body and focus rather on fatty acid intake, antioxidant intake, theracurmin and high dose, phospholipid DHA, phosphatydil choline and Alpha GPC, all of which are hard to overdose on and which heal the blood brain barrier and mitigate oxidative damage in the brain itself. Everyone has different clearance rates for compounds in the liver. Once weekly may still be too much or not enough.