Hypothesis that deficiency of Innate Immunity protein causes AD

[frankiesfriend]

“An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer’s disease – a cohort study of 95,442 individuals.” 2018. Alzheimer’s & Dementia. Rasmussen, K., et al. pages 1 – 13.

My non-expert analysis of this research article.

Complement C3 is a protein that (along with other proteins) regulates the immune response. Complement C3 is the “master regulator”, typically the first to be activated in response to infection or inflammation. The authors of this paper propose a theory that low Complement C3 levels - measured in serum at baseline -increase the risk of development of Alzheimer’s Disease (measured after 8 years follow up in the Copenhagen Heart Study population). They report that low levels of Complement C3 at baseline increases the risk of Alzheimer’s mildly in E3/E3, slightly more in E3/E4, and dramatically in E4/E4. The authors speculate that Complement C3 deficiency hobbles the immune response in the brain, and that E4/E4’s are more severely affected because they may have more difficulty with maintenance of brain health. The authors postulate that the observed complement deficiency is not just a correlation, but is causal of development of AD wherein the immune response in the brain is inadequate to address inflammation or infection.

The author’s analysis indicates that being E4/E4 does NOT mean one would have low Complement C3, but instead they are saying that being E4/E4 AND having low baseline Complement C3 increases risk of disease. They calculate that increased risk to be 1.66 for those E4/E4 individuals with Complement C3 that is 1 standard deviation below the average (meaning that one would have lab values in the low end of normal – wouldn’t raise eyebrows in the doctor’s office).

Complement is a test usually ordered when an immune system dysfunction is suspected – multiple sclerosis, lupus, vasculitis, etc. Complement would probably test high in the case of chronic infection or inflammation, and would possibly be accompanied by high WBC and/or elevated CRP. I have been tested twice because of symptoms that might have been explained by immune dysfunction. My Complement C3 tested low outside-of-normal-range – very low according to this paper - where “low” is defined as values in the low end of the range for normal lab values. For me, there was no unusual value for anything else in my labs, and there was no explanation that would connect this lab value to my symptoms at that time, so it remains in my medical history simply as medical anomaly that my primary care doctor can’t explain, but that these authors would probably posit is genetic. According to this study, my "very low" test results put me at 10 times the risk of Alzheimer’s as those with higher Complement C3 if it turns out that I am E4/E4. I am expecting the DNA results in early February.

If we are never tested for Complement except when we are sick, it is unlikely that we will know our “baseline” values. For example, Complement C3 lab values can be low like mine because the levels are chronically deficient, or they can be temporarily low if the protein is depleted (from a normal value) by an infection. If mine had been depleted, an earlier baseline value, if one had been taken, would presumably have been higher. I tend to think that my levels are deficient since I had no lab results that indicated inflammation or infection.

I would be interested in reading opinions of this research. In particular, I got pretty lost in understanding the statistics they use, and I am always wary of studies that include measurements taken from a population that includes participants too young to develop dementia (yet). The researchers report that they stratified the age groups but not which ages were used in the analysis. Also, there was a difference of effect magnitude of low-Complement/E4E4 between two populations that they studied. That is worth further evaluation. Lastly, is a lab value taken eight years before onset of AD actually a baseline value?

I am also interested in the "gut microbiome" discussion in another thread, wondering if this is a potential path to altering the Complement genetic expression.

[SusanJ]

This one got my attention. I've looked at the complement system several years back with regards to it's links to autoimmune disease.

According to this University of Rochester post, inherited deficiency is quite rare and C3 deficiency is most likely due to recurrent bacterial infections.
(See https://www.urmc.rochester.edu/encyclop ... t_c3_blood)

With the very recent posts on Porphyromonas gingivalis and H. pylori links to AD, perhaps a link? But this is certainly something to watch.

There is also a link to macular degeneration, another amyloid related disease. Here's the full text article from 2018, along with snps that might be related.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199710/

If I can find some spare time, I plan to dig a bit more on this one.

[SusanJ]

Hmm, and plant lectins can also activate the complement system...another place to dig and see if lectins lower complement C3 levels over time, especially for those who might be genetically predisposed to it.

Plant lectins, otherwise known as phytohemagglutinins or hemagglutinins, have been shown to possess a remarkable array of biological activities. In vitro they have been shown to effect lymphocyte mitogenesis (both stimulating (1) and inhibiting (2), with the
lymphocytes of the gastrointestinal tract being the most susceptible (3)), to possess the ability to aggregate immunoglobulins (4), to trigger the alternate complement pathway (5), to inhibit fungal growth (1), and to induce histamine release from basophils and mast
cells (6).

https://academic.oup.com/ajcn/article-a ... m=fulltext (doesn't look like the full text is free anymore, so go to your favorite repository for a copy).

[SusanJ]

And here's another nasty that doesn't play nice with complement C3: Candida albicans.

Thus, upon infection C. albicans uses Pra1 to destroy C3 and to disrupt host complement attack. In conclusion, candida Pra1 represents the first fungal C3-cleaving protease identified and functions as a fungal master regulator of innate immunity and as a central fungal immune-escape protein.

https://www.ncbi.nlm.nih.gov/pubmed/28860090

[Julie G]

Great find, FF! This one had me falling down a rabbit hole... surfacing for air and I haven't fully absorbed it yet

The author’s analysis indicates that being E4/E4 does NOT mean one would have low Complement C3, but instead they are saying that being E4/E4 AND having low baseline Complement C3 increases risk of disease.

That's not quite my take. Per the authors, (at least) two other papers do indicate that E4 is associated with low plasma C3 via several gene pathways:

Our finding that low plasma complement C3 is associated with high Alzheimer’s disease risks particularly in highly susceptible individuals carrying the APOE ε44 genotype is in line with previous findings. In one study, a coding variant in the CR1 gene (Ser1610Thr, rs4844609) was associated with episodic memory decline, largely dependent on interaction with APOE ε4 and mediated by increased burden of Alzheimer’s disease–related neuropathology. In accordance with this, one study found interaction between APOE ε4 and rs6656401 (which may also be a surrogate marker for rs4844609), another study found that the CR1 SNP (rs3818361) did only associate with Alzheimer’s disease in APOE ε4 carriers whereas a third study did not pick up this interaction. Because both the APOE polymorphism and CR1 variation are associated with amyloid and tau pathology, it seems biologically plausible that effects of a decreased capacity or activation of the complements system could be additive to effects of defective apoE, and that a decreased capacity or activation of the complements system is not sufficient to disturb the homeostatic mechanisms of brain maintenance under normal conditions; however, for a challenged brain maintenance, this might become especially crucial. 


You can read more about the genetic association with ApoE4 here. You can see that rs4844609AA combined with ApoE4 greatly magnifies risk. The bad news is that even TT increases risk substantially.

dds05404-2.jpg

I'm not buying the theory that ApoE4 is associated with a lowered innate immune response when so many papers, like this have come to the opposite conclusion, even leading Dr. Bredesen to label E4 "the pro-inflammatory allele." My guess is that our innate immune system can become depleted when exposed to overwhelming infection or chronic infection such as that described by Dr. Bredesen’s third subtype/Toxic (CIRS) which he now believes is responsible for the majority of Alzheimer’s. I’m CIRS positive due to a Babesiosis infection and have crazy high C4a, but to my knowledge have never had my C3 measured. I did have my C3a (related) measured and it was very low- 29 (reference range 55-486 ng/mL) which leads me to believe I may also fall into the low C3 category.

Hmm, and plant lectins can also activate the complement system...another place to dig and see if lectins lower complement C3 levels over time, especially for those who might be genetically predisposed to it.

My guess is YES based upon my observations above. This is likely one of those cases where we want to suppress C3 activation, not activate it. That said, it’s fascinating to see that dietary lectins are one way of activating the C3 pathway, possibly lending credence to Dr. Gundry’s clinical work.

Overall, this paper paints a pretty dire picture for those with 4/4:

1. Systematic review: We searched PubMed for articles published in any language with search terms complement C3 and dementia, as well as related terms. Reference lists of articles identified in the literature search were further reviewed. No relevant human studies were identified.


2. Interpretation: Low baseline levels of complement C3 were associated with increased risk of Alzheimer’s disease in individuals from the general population. The risk of Alzheimer’s disease associated with low C3 was amplified in high-risk individuals with APOE ε44 genotype. These epidemiological findings were substantiated by a Mendelian randomization approach, thus implying causality. 


3. Future directions: Using prospective general population data, we suggest that low plasma complement C3 marks a causal pathway for development of Alzheimer’s disease, which becomes overt especially in APOE ε44 high-risk individuals. Future studies should explore the mechanism behind these findings.[Emphasis mine.] 


Identifying and addressing any underlying infections as well as avoiding or addressing insulin resistance (both of which activate C3) seem to be our best strategies.

[circular]

The authors of this paper propose a theory that low Complement C3 levels - measured in serum at baseline -increase the risk of development of Alzheimer’s Disease

Susan and Julie I'm cornfused. If lectins stimulate C3 they would appear to be a way to address low C3 that seems to predispose to AD. I'm really exhausted today. Am I missing something?

[circular]

C3 direct to consumer available for a price at Life Extension. https://www.lifeextension.com/Vitamins- ... plement-C3

Haven't looked elsewhere.

[Julie G]

Susan and Julie I'm cornfused. If lectins stimulate C3 they would appear to be a way to address low C3 that seems to predispose to AD. I'm really exhausted today. Am I missing something?

Susan and I are making the assumption that the C3 depletion is the result of over-activation in much the same way that excess insulin leads to insulin resistance. Many papers support the idea that E4 is associated with a GREATER innate immune response. I just sent the paper to Dr. Bredesen to get his take.

[circular]

Susan and Julie I'm cornfused. If lectins stimulate C3 they would appear to be a way to address low C3 that seems to predispose to AD. I'm really exhausted today. Am I missing something?

Susan and I are making the assumption that the C3 depletion is the result of over-activation in much the same way that excess insulin leads to insulin resistance. Many papers support the idea that E4 is associated with a GREATER innate immune response. I just sent the paper to Dr. Bredesen to get his take.

Thanks for the clarification Julie!

[SusanJ]

Yep, over-activation leads to depletion. So, the challenge is to figure out how to catch the ramp up at the "right" point, and allow the body to ramp back down before the complement system runs out of steam.

You see that response in sepsis, too, from what I've read. Complement C3 depletion after the original assault.

With greater innate immune response (e.g. E4), we might be hitting bottom more quickly, which increases our risk for bad outcomes.