New research identifies fibronectin as a potential link between APOE4, inflammation and blood-brain barrier dysfunction—and points toward some intriguing possibilities for prevention research.
Does Dr. Green have an age recommendation for when apoe4 carriers should start low dose rapamycin? And I was also thinking the other day that maybe the mild immune suppression actions of rapamycin are healthy for apoe4 carriers due to our genetic predisposition to an overactive, overly alert immune system to begin with. I saw this article on fibronectin and apoe4 a while back but did not connect it to mTOR until you mentioned it in this article. I think that you may have found one of the most effective pathways in mTOR regulation to control this fibronectin overgrowth. 🙌
Recent research on direct action of nattokinase on Fibronectin and FN1. It may not cross normal bbb directly but the interface / structure of BBB junctions etc might be benefited as might the FN1 down regulation . There may also be indirect beneficial impact. (See also CurQfen a patented highly brain absorbable form of Curcumin with research published on positive cognitive impacts and highly anti inflammatory and possibly anti amyloid hence might reduce Fibronectin deposition directly or indirectly.)
“Nattokinase‑driven remodeling of tumor microenvironment enhances
the efficacy of MSLN‑targeted CAR‑T cell therapy in solid tumors
Thank you Karin , very useful. I am considering starting low dose weekly rapa and wondering what is the target blood level Dr Green tried to achieve? Also if you have any info on protective gene mutations affecting Fibronectin so I can search on full genome. I will also look and share if finding any mutations by rs number? Thanks again.
Thank you, I saw that in the paper now and will search generally that gene and update. I have found a paper suggesting nattokinase can break down Fibronectin but will check out further
Nattokinase cannot cross the bbb. It is a moderate systemic fibrinolytic pretty much everywhere the blood flows except in the brain, unfortunately. But keep in mind that excess fibronectin is stimulated by unattenuated oxidative stress and inflammation in the brain. NAC, R-alpha-lipoic acid and liposomal curcumin are phenomenal mitigating actors against this type of inflammation and oxidative stress in the brain, and phospolipid bound DHA can help to heal a damaged bbb. And really, this is where the benefits of low dose rapamycin, I believe now, shines the greatest, in down-regulating the mTOR pathway so that astrocytes are not stimulated to produce abnormal amounts of fibronectin in the first place.
There is an FN1 gene variant that is protective - but it's quite rare... I didn't take note of the rs#.. As for the rapamycin: Dr. Green didn't check blood levels. Instead, he kept an eye on neutrophils not getting too low and having a Z-Pak onhand in the event one had an unexpected bacterial infection. I've never had an issue. My neutrophils were initially trending a bit low in the first year on rapa. Now they've adapted and stay in the normal range. 6mg, one day a week is the dose I'm on.
Thank you for this article. It makes sense to treat the consequences of having APOE4 for prevention purposes since we can’t readily change the gene. Did you say that you were taking Rapamyacin? On that note I would love to know all that you have been doing for prevention purposes. You are obviously doing the right things being your blood test taken in Florida came out so well. 😊
yes, I am taking rapamycin - once weekly since 2021. I've consolidated my prevention protocol, and update as I change things on the members site, members.apoe44.org
Does Dr. Green have an age recommendation for when apoe4 carriers should start low dose rapamycin? And I was also thinking the other day that maybe the mild immune suppression actions of rapamycin are healthy for apoe4 carriers due to our genetic predisposition to an overactive, overly alert immune system to begin with. I saw this article on fibronectin and apoe4 a while back but did not connect it to mTOR until you mentioned it in this article. I think that you may have found one of the most effective pathways in mTOR regulation to control this fibronectin overgrowth. 🙌
The late Dr Green was adamant that every APOE4 carrier be on rapamycin starting midlife (women after menopause).
So far the best argument for apoe4 carriers to take low dose and cycled rapamycin regardless of cognitive capability status.
On the hunt to see if nattokinase might be useful ( am already taking ) in this regard - still looking
Nattokinase attenuates endothelial inflammation through the activation of SRF and THBS1
Hui-Wen Chiu a b c d,
Chu-Lin Chou d e f g
,
Kung-Ta Lee h
, Chun-Che Shih i j k,
Tzu-Hsuan Huang a
, Li-Chin Sung d i l m n
Show more
I also take it (in Neprinol)... it won't hurt (should not be taken without doctor's ok if one is on blood thinners.)
Recent research on direct action of nattokinase on Fibronectin and FN1. It may not cross normal bbb directly but the interface / structure of BBB junctions etc might be benefited as might the FN1 down regulation . There may also be indirect beneficial impact. (See also CurQfen a patented highly brain absorbable form of Curcumin with research published on positive cognitive impacts and highly anti inflammatory and possibly anti amyloid hence might reduce Fibronectin deposition directly or indirectly.)
“Nattokinase‑driven remodeling of tumor microenvironment enhances
the efficacy of MSLN‑targeted CAR‑T cell therapy in solid tumors
Lianfeng Zhao1 · Yan Zhang1 · Xinhao Yang1 · Tianyu Chen1 · Jiaqi Liu1 · Zhigang Guo1
Received: 29 July 2025 / Accepted: 3 September 2025 / Published online: 29 September 2025
NKase disrupts tumor‑associated fibronectin
to enhance MSLN CAR‑T cell infiltration
By analyzing the gene expression of tumor cells treated
with NKase, we found that the gene FN1 was decreased,
which indicated a reduction in the ECM component
fibronectin protein [44,”
Thank you Karin , very useful. I am considering starting low dose weekly rapa and wondering what is the target blood level Dr Green tried to achieve? Also if you have any info on protective gene mutations affecting Fibronectin so I can search on full genome. I will also look and share if finding any mutations by rs number? Thanks again.
Thank you, I saw that in the paper now and will search generally that gene and update. I have found a paper suggesting nattokinase can break down Fibronectin but will check out further
Nattokinase cannot cross the bbb. It is a moderate systemic fibrinolytic pretty much everywhere the blood flows except in the brain, unfortunately. But keep in mind that excess fibronectin is stimulated by unattenuated oxidative stress and inflammation in the brain. NAC, R-alpha-lipoic acid and liposomal curcumin are phenomenal mitigating actors against this type of inflammation and oxidative stress in the brain, and phospolipid bound DHA can help to heal a damaged bbb. And really, this is where the benefits of low dose rapamycin, I believe now, shines the greatest, in down-regulating the mTOR pathway so that astrocytes are not stimulated to produce abnormal amounts of fibronectin in the first place.
There is an FN1 gene variant that is protective - but it's quite rare... I didn't take note of the rs#.. As for the rapamycin: Dr. Green didn't check blood levels. Instead, he kept an eye on neutrophils not getting too low and having a Z-Pak onhand in the event one had an unexpected bacterial infection. I've never had an issue. My neutrophils were initially trending a bit low in the first year on rapa. Now they've adapted and stay in the normal range. 6mg, one day a week is the dose I'm on.
Thank you for this article. It makes sense to treat the consequences of having APOE4 for prevention purposes since we can’t readily change the gene. Did you say that you were taking Rapamyacin? On that note I would love to know all that you have been doing for prevention purposes. You are obviously doing the right things being your blood test taken in Florida came out so well. 😊
yes, I am taking rapamycin - once weekly since 2021. I've consolidated my prevention protocol, and update as I change things on the members site, members.apoe44.org