Lectins and AD - Exploring a Potential but Unproven Connection

[Tincup]

Thanks Circ! I've added these to the list of questions for our July Gundry call. It dawned on me I should state up front I'd like him to provide a way for us to locate references when we talk. Most of his patients would not want this level of detail. I should be clear that we do at the beginning of our call.

[circular]

This is the first I've heard of the call. Can you point me to details or put them here? Oh wait, you must mean a followup consult for you and your bride?

[Tincup]

This is the first I've heard of the call. Can you point me to details or put them here? Oh wait, you must mean a followup consult for you and your bride?

Yep

[circular]

Here's my next installment. Too tired to polish it up much:

I’ve been digging a little deeper into the question of whether, at least in some people, lectins might play any conceivable role(s) in AD brain pathology. Dr. Gundry indicated to me that lectins can play a roll, at least in some people. I think he mentioned them damaging the vasculature in the brain. If true, this would most likely impact the blood-brain barrier and could contribute to downstream effects that could participate in AD pathology. As many here know, he identifies lectin-sensitive people using an adiponectin measurement. In his view, high adiponectin signifies lectin sensitivity, and that can spell danger for long term health.

While Dr. Gundry hasn’t detailed how adiponectin relates to lectin sensitivity, it seems clear that there’s a concern with respect to adiponectin and dementia in some people. The problem for me and many others, which I learned about through Dr. Gundry, is presented in the Framingham data (840 subjects) showing that high adiponectin in women is a risk factor for dementia, independent of e4 status and other risk factors. Since my adiponectin is very high, I'm female, and I already carry additional risk factors for AD including a family history, I had to sit up and take notice.

In fact Dr. Gundry is the only one I know of who is consciously trying to address the adiponectin paradox in women (thin women in particular), safely, at the clinical level. For now, if destroying lectins (pressure cooking) or avoiding them may potentially mitigate this independent risk factor I have for AD, it will have been worth it to me. I’ve enough concern dealing with e4 and a family history.

The Framingham paper appears to be the source of Dr. Gundry’s desire to see adiponectin levels <16 mg/L. The means in the subjects were for men 10.6 (2.5–36.0), and for women 16.5 (4.0–60.8). It reports:

Results of quartile analyses of adiponectin level in women showed a threshold at the median. Women with a baseline adiponectin concentration more than the (sex-specific) median had a significantly higher risk of all-cause dementia and AD even in the fully adjusted model (HR, 1.63; 95% CI, 1.03–2.56; P = .04 and HR, 1.87; 95% CI, 1.13–3.10; P = .01, respectively) (Table 7)

He also appears, possibly, to be choosing some biomarkers to test in his patients based, at least in part, on this study: adiponectin, glucose, glycated albumin, insulin, Lp-PLA2 and CRP (not that these aren’t commonly considered for various reasons).

So what we have here, more or less is this formula in search of a proof:

(Women + High APN = Dementia/AD [Framingham]) + (High APN = Lectin Sensitivity [Gundry]) = Lectins may have a role in AD

It’s been my impression from him that Dr. Gundry is having a hard time getting some in the research community to turn their focus to the dark side of adiponectin hinted at in the Framingham data. High adiponectin is valued and reported as a sign of insulin sensitivity, because it's low in the context of metabolic syndromes and overweight. If your level is high, male or female, the labs will tell you that's great. In fact a doctor three years ago tested my adiponectin (I don't know why), it was high, and the lab range 'informed' me that my result was stellar. I felt good about it and went on. Never take a commercial blood lab at face value?

Based on a cursory look into what turns out to be something like over 9000 studies mentioning adiponectin, it seems that much about adiponectin appears to remain uncertain, and there seems to be even much less about lectins and neurodegerative disease (I’ve posted one such paper earlier in this thread that provides a worm model for lectin activity in Parkinson’s).

Adiponectin was only discovered in the 90s, despite the fact that it's a large and complex molecule with relative abundance in the blood. It's characterized by seemingly opposing functions/effects and is described as pleiotropic, making it quite complex. It's being studied quite heavily with a lot more work to be done to understand and characterize it well. I suspect that as this work continues there likely will be many points of views and disagreements over the years it will take to iron it out in all its complexity using the reductionist, peer-reviewed research model. That's certainly the goal but we’ll have to be patient with the process.

Here’s what I found about adiponectin’s dark side in my cursory look into the quite mixed literature. This article describes high adiponectin in the context of 'classic' autoimmune/inflammatory conditions and may suggest something about his line of thinking:

'Adiponectin and inflammation: Consensus and controversy' (2008)

In contrast with disorders typically associated with excess adiposity and positive energy balance, adiponectin levels are elevated—rather than decreased—in classic chronic inflammatory/autoimmune diseases that are unrelated to increased adipose tissue, such as rheumatoid arthritis, SLE, inflammatory bowel disease, type 1 diabetes, and cystic fibrosis [add CIRS???]. In these patients, adiponectin levels positively—rather than negatively—correlate with inflammatory markers. Furthermore, proinflammatory effects of adiponectin have been reported in tissues such as joint synovium and colonic epithelium. Thus, adiponectin is regulated in the opposite direction and may exert differential functions in classic versus obesity-associated inflammatory conditions. [Emphasis added]

This will make a light bulb go off for those who've come across many other venues linking lectins to gut damage and autoimmune/inflammatory disorders, with what degree of established science I don't know.

(I will appreciate anyone taking the time to closely review this article for any weaknesses and/or strengths.)

An interesting letter discussing this article was published later that year:

'Adiponectin: A defense protein in catabolism'

Insulin increases lipogenesis and synthesis of glycogen and proteins. These anabolic effects can only be exerted when substrates (ie, food) are available. Adiponectin, on the other hand, as postulated by me and lately also by others, is a protective protein in catabolic states, such as starvation.3, 4

There's much more in this letter I haven't had a chance to wrap my brain around, as it begins to describe adiponectin in both an evolutionary context as well as with respect to ketogenic/calorie restricted/fasting diets vs. energy abundance and glucose burning. It may provide a bridge from the classic inflammatory conditions, where high adiponectin is positively correlated with inflammatory markers, to metabolic states and brain disease???

Next this:

'Adiponectin receptor signalling in the brain' (2012)

Adiponectin is an important adipocyte-derived hormone that regulates metabolism of lipids and glucose... Adiponectin has been shown to exert a wide range of biological functions that could elicit different effects, depending on the target organ and the biological milieu. There is substantial evidence to suggest that adiponectin receptors are expressed widely in the brain…

A recent study by Une et al. (2010) demonstrated the presence of adiponectin in mild cognitive impairment and Alzheimer's disease (AD) patients. They analysed adiponectin in plasma and CSF from cognitively normal controls (NC), subjects with mild cognitive impairment (MCI) and patients with AD. They found that plasma adiponectin was significantly higher in MCI and AD compared with NC, whereas CSF adiponectin was significantly higher in MCI compared to NC. These higher adiponectin levels in plasma and CSF in MCI and AD patients is intriguing and could suggest that this molecule plays a role in the onset of AD. The authors also suggested that the weight loss and lower body mass index seen in elderly AD patients, and the correspondingly high level of adiponectin during the same period, could point to a role for adiponectin during the pro-dromal state of AD by altering the CNS control of energy homeostatsis and body weight (Aziz et al., 2008; Luchsinger, 2008; Luchsinger and Gustafson, 2009a,b) (Figure 5).

[Next discusses a study contrarily showing low plasma adiponectin along high adiponectin receptor activity in the brain and beneficial effects…]

Although that study shows a beneficial effect of adiponectin [in the brain] and is in stark contrast to our studies, the up-regulation of AdipoR1 in this model, too, suggests the possibility that adiponectin and its receptors may not be mere spectators in neuronal regulation during physiological and pathological processes, but they may have a larger and more definitive role in the functioning and maintenance of the brain… [would like to listen to Dr. Gundry and Dr. Bredesen discuss this!]

The level of adiponectin in CSF does not appear to correlate with the level in plasma (Hietaharju et al., 2010)… [Emphasis added]

With respect to that last point, there seems to be confusion about whether adiponectin can cross the blood-brain barrier:

‘Secret talk between adipose tissue and central nervous system via secreted factors—an emerging frontier in the neurodegenerative research’ (2016)

Concerning adiponectin, its capacity to cross the BBB is questionable. In one study, the results based on the measurement of radioactive labeled adiponectin and concentration in the cerebrospinal fluid indicate that adiponectin does not cross the BBB but will affect the cells of the BBB and indirectly affect the CNS acting via AMPK pathway [9, 138]. In another work using adiponectin KO mice and recombinant adiponectin, it is shown that adiponectin crosses the BBB [191]. As the conclusion, these two publications proposed opposite results concerning the possibility of adiponectin to cross the BBB, and more conclusive results will be needed to clarify this point.

Another paper in this context to post for now. Dr. Gundry has said he talks about lectins and Parkinson's in his upcoming book, so that's good:

This article touching on lectin and PD in worms offers an explanation for why some people may be more sensitive to lectins than others:

Differences in inherited sugar structures of gut and neuronal cell surfaces may make some individuals more susceptible in this conceptual disease etiology model.

Maybe such a hypothesis (lectin sensitivity > inflammatory illness > high adiponectin and inflammatory markers in the brain) will eventually be more widely seen if not accepted as describing another face of inflammatory AD?

So that’s all I have the energy or time for, for now … This is so beyond any training I have haha!

We basically have at least two pathways that I can imagine that lectins might take to contribute to AD pathology, theoretically for now: via damage to the vasculature of the brain (and thus probably BBB?) and via the vagus nerve.

[Julie G]

Nice overview! Thanks for your efforts, Circ. The more I explore adiponectin, the more confused I am. A cursory look at adiponectin within the context of my very high TGF-Beta1 suggests that high levels are protective? My guess is that adiponectin is neither friend, nor foe; but a player in controlling inflammation. Because lectins cause inflammation in sensitive individuals (me! ) it makes sense that they'd be higher in this group.

Adiponectin inhibits oxidative stress and modulates TGF-b1 and COL-1 expression via the AMPK pathway in HSC-T6 cells
http://www.ncbi.nlm.nih.gov/pubmed/25751391

[Stavia]

Thanks for digging into this rabbit hole Circ. It's clearly not as simple as Gundry's opinion and also clearly still poorly understood. I suspect Gundry's book will be a rehash of his poster data but let's see...
It may or may not be a significant biomarker in AD prevention. Just because there is a possible theoretical mechanism doesn't make it true.

It does look however that it may be a significant marker and possibly a player in some inflammatory states.

Sorry to be skeptical but I truly believe the evidence isn't here yet, just a lot of data that scientists are trying to interpret.

This obviously leaves you with a choice - just as many of us had the HRT choice to make where not taking HRT may have had a negative consequence.
I guess you have to balance symptoms and possible harms....pressure cooking beans especially if one has autoimmune or inflammatory conditions isn't such a big harm if you physically feel better for it Circ. But I strongly feel that the science isn't there yet to say that everyone should do it as part of their apoe4 anti-AD primary prevention strategy.

[MarcR]

I have not read anything indicating that Dr. Gundry sees adiponectin as a therapeutic target. I think he just sees it as an indicator that lectin avoidance may be a useful tool to reduce systemic inflammation. The actual therapeutic target biomarker is TNF-alpha.

I do think adiponectin is an interesting topic generally and applaud circular's efforts here.

[Tincup]

I have not read anything indicating that Dr. Gundry sees adiponectin as a therapeutic target. I think he just sees it as an indicator that lectin avoidance may be a useful tool to reduce systemic inflammation. The actual therapeutic target biomarker is TNF-alpha..

That is clearly true in our conversations with Gundry - he does not see adiponectin as a therapeutic target. He does target TNF-alpha.

Circ, thanks for all your work!!!

[Julie G]

Marc, George- that is my understanding as well. Thanks for the clarification. I've never tested my adiponectin level, but I'm riddled with pain when I indulge in lectins . Cashews and pistachios are the worst. I suspect Gundry is onto something.

[circular]

Never fear Stavia, I’m also not saying that lectins cause dementia or that adiponectin has been proven to be a marker for lectin sensitivity. Still, understanding, if and when possible, why high adiponectin levels in thin women are correlated with dementia seems critical, but that’s not to say that the reason is certainly lectins. I think it’s more complex than that, in that lectin input may just be a physiologic process modifier, at least in some people. That what I mean by 'connection' in the modified thread subject line.

The more I explore adiponectin, the more confused I am.

Agree! In fact I’m beginning to wonder if Adiponectin itself is confused! I have a few more things to add, but probably most important is that I realized I am obviously, woefully under-prepared to take on this quixotic phantom! It seems that however I approach it I bump up against a contradiction, or two, or three. Not only does it seem to be a phantom, I’m wondering if it’s floundering in its evolutionary purpose in the midst of modern, industrial inputs, and we get mixed up by trying to give it more credit than it deserves while being pinned to the mat by our various inflammatory states!

A cursory look at adiponectin within the context of my very high TGF-Beta1 suggests that high levels are protective? My guess is that adiponectin is neither friend, nor foe; but a player in controlling inflammation.

Take a gander at Wikipedia mobile view's long list for adiponectin under 'Biological Process' (for some reason this list isn't on the desktop page). It seems that when we see molecules such as this that are involved with regulation we get into paradoxical behaviors, and adiponectin appears to be involved in not just one but a number of regulatory processes.

I might rephrase your guess to 'adiponectin is neither friend, nor foe, but involved with the regulation of many biological processes, including inflammation and energy homeostasis, and appears in many guises, and doesn’t always play its role well in modern contexts.’ (That last phrase is supported by nada hard data!) For instance, why, as an anti-inflammatory cytokine, is it low in the metabolic, insulinemic inflammatory environment while high in the 'classic' immune inflammatory environment?

It seems based on the WikiP article (which makes quite a few interesting statements!) that adiponectin molecules clump together to varying degrees, so there are different forms of adiponectin, and different adiponectin receptors, and adiponectin gene snps. It having various forms seems reminiscent of what happens when you look under the hood of LDL or HDL. You find good and bad players and context can influence interpretation. Maybe one day we’ll be ordering an adiponectin panel

What the letter seems to be doing is trying to resolve the paradox that both low and high adiponectin are flags for different types of inflammatory states by reframing adiponectin in the evolutionary context with respect to aberrant anabolic and catabolic states. I'm trying to read between the lines. As with Dr. Gundry’s pithy statements, there’s a lot of what should be logic left out and it doesn’t seem to me to add up on its face.

Insulin increases lipogenesis and synthesis of glycogen and proteins. These anabolic effects can only be exerted when substrates (ie, food) are available. Adiponectin, on the other hand, as postulated by me and lately also by others, is a protective protein in catabolic states, such as starvation.3, 4

Maybe as a regulator of energy homeostasis, and in ideal, stable and evolutionary energy conditions, adiponectin activity (not necessarily snapshot test results) might have a somewhat restricted range either side of the mean, addressing moderate fluctuations in food supply and inflammatory triggers. Then, in our modern, industrialized context, it can take off aberrantly in either direction:

• Maybe, in the modern, post-neolithic context of an overabundance of nutritional energy, physiology turns too far in the anabolic direction (metabolic syndrome) and adiponectin is driven down. (In this case maybe there are heavier people with metabolic syndrome who are also lectin sensitive but their adiponectin will remain low because of their anabolic state.)
  
  While also,
  
  Maybe in the modern, post-neolithic context of high dietary lectins (especially from grains and usually not mitigated by traditional cooking methods), lectins chronically damage the gut barrier of those with vulnerable genetics and enter the bloodstream, stimulating an ongoing immune attack against these molecules that don’t fit our inherited molecular signaling playbook. In such an attack, physiology may turn too far in the catabolic direction, where adiponectin then goes too high in an attempt to redress the damage. (My thinking here does not address why adiponectin stays high in people who are ‘off’ lectins. Did we not evolve a molecular switch to turn it off once activated by the neolithic legumes?)

Adiponectin … is a fuel-providing hormone in catabolic states, and its levels are consequently increased.

But why is high plasma adiponectin correlated with advanced disease states such as dementia and no doubt advanced 'classic' immune conditions? If it’s protective why are things going so badly over the long term? Either it’s just an oversimplification of a complex molecule, or the sucker is no match for the modern world, trying in vain to balance us out. What culprit(s) prevent it's anti-inflammatory nature from knocking out the illnesses?

I haven’t yet pondered how e4 hypometabolism of brain glucose might fit into this context. That’s probably good for us all