ApoE4 in patients with Marfan Syndrome?

[Julie G]

Julie you're my alter ego. Every time I try to rationalize something not being the case you present data to make me question The cup of coffee at my side is dedicated to you!

LOL, I'll drink to that . I think this connection may be important. Collagen is like scaffolding. It's what holds our body together. Could a reduction make everything (our gut, our tendons, our blood vessels, our BBB, etc.) more permeable? Another angle to consider is the role of mast cells. You know they're primarily found in connective tissues. So many of our members also have mast cell or histamine issues. Could this be what mediates the pro-inflammatory aspect of our allele? I'd love to investigate the prevalence of connective tissue disorders by APOE genotype. When I get a chance, I want to track down more specifics and share the hypothesis more broadly.

[circular]

Collagen is like scaffolding. It's what holds our body together. Could a reduction make everything (our gut, our tendons, our blood vessels, our BBB, etc.) more permeable? Another angle to consider is the role of mast cells. You know they're primarily found in connective tissues. So many of our members also have mast cell or histamine issues. Could this be what mediates the pro-inflammatory aspect of our allele? I'd love to investigate the prevalence of connective tissue disorders by APOE genotype. When I get a chance, I want to track down more specifics and share the hypothesis more broadly.

Completely agree about the pervasive permeability/poor connective tissue problem, but it seems to me that for most connective tissue disorders, mutations among the many connective tissue genes are probably enough to explain any high prevalence among us, independent of e4. I would think an e4 connection to CTDs generally would already have been noted by the connective tissue genetics researchers, but maybe they've not looked at enough genes to find a connection that may be there? A connective tissue geneticist I saw this winter said in genetics the 'low hanging fruit' has been found. That's why they've moved on to polygenetics. (I may not be paraphrasing her just right.) I would think e4 would be among the low hanging fruit, but it's never included in CTD genes. In your exploration it would be interesting to talk to a CTD geneticist about just what genetic surveys have included.

The whole overlap comes together in my mind if we separate out CTDs with known genetic determinants from hypermobility and associated weak connective tissue problems that are often seen in the absence of known CTD genes. If Dr. Afrin is correct, I can connect the dots broadly from e4 to mast cells to weak connective tissue. He believes that those with hypermobile EDS, for which a gene hasn't been found (and which we know includes 'everything' from gut to ligaments to blood vessels), are suffering from connective tissue remodeling caused by the many inflammatory chemicals produced during aberrant mast cell activation. Then the question is whether e4 directs mast cells to be trigger happy as part of its 'host-protective' inflammatory mechanism. If Dr. Afrin's right this seems plausible.

Today I was reading about TMJ, having recently developed this very unwelcome new problem, associated no doubt with my EDS. TMJ.org makes an interesting comment about comorbid conditions:

Scientists have found that most patients with TMD also experience painful conditions in other parts of the body. These comorbid conditions include chronic fatigue syndrome, chronic headache, endometriosis, fibromyalgia, interstitial cystitis, irritable bowel syndrome, low back pain, sleep disorders, and vulvodynia. [They left out mold, Lyme, MARCoNS ...!]They are considered comorbid because they occur together more often than chance can explain. In addition, the conditions share other features. [Such as?] These findings are stimulating research into common mechanisms underlying all of these comorbid conditions. Indeed, other research indicates that TMD is a complex disease like hypertension or diabetes involving genetic, environmental, behavioral, and sex-related factors. Note that many of the comorbidities mentioned are more prevalent or occur exclusively in women. [As with AD.]
...

Research to understand why these conditions coexist is in its early stages, but it is already prompting leading investigators to propose a name change. “TMD” is not an apt term to describe the complex multisystem pains and dysfunctions that many patients experience. The thinking now is that these debilitating problems experienced in various parts of the body have their origin in pathology at the highest levels of the brain and central nervous system.
[Emphasis added.]

It would be interesting to pick these researchers' brains!

[circular]

Okay so here's a page at TMJ.org addressing: 'The thinking now is that these debilitating problems experienced in various parts of the body have their origin in pathology at the highest levels of the brain and central nervous system.' It's getting a bit far afield, but the way the CNS generally and maybe e4 specifically can be involved in many peripheral conditions will probably become clearer and clearer.

The investigators found a number of gene variants that may be predictive of TMD pain. Most of them are related to neurotransmitters (chemical messengers that neurons use to communicate) or to inflammation pathways. Other studies have shown that TMD patients with a more centralized pattern of pain have higher levels of inflammatory markers. These studies support the idea that centralized TMJ pain may be exacerbated or maintained by changes to neurotransmitters or inflammation in the brain.

The paper she refers to illustrates the genetic complexity I think we'll find looking at root causes of non--CTD-gene hypermobility/weak connective tissues that may result from inflammation and even CNS processing mechanisms:

Given the multifactorial nature of TMD, a large number of genetic variants are expected to
contribute to the risk of TMD onset and persistence13, Advances in high throughput
genotyping methods have led to discoveries that numerous genes are associated with TMD
depression, anxiety, stress response, somatic awareness, affective disorders, and chronic
pain has increased within the last few years. The same psychological characteristics are
hypothesized to be intermediate phenotypes for TMD in the OPPERA heuristic model. A
partial list includes genes that encode serotonin transporter (5-HTT) 7, 27, 41, cyclic AMPresponse
element binding protein 1 (CREB1) 75, monoamine oxidase A (MAOA) 10, 38,
serotonin 1A and 1B receptors27, 41, 52, 68, catecholamine-O-methyltransferase (COMT)
1, 11, 14, 30, 31, 38, 48, GABA-synthetic enzyme GAD6565, D2 dopamine receptor (DRD2)
40, glucocorticoid receptor (GR) 73, interleukines 1 beta (IL1β) and alpha (IL1α) 47, 62, 74, interleukine receptor antagonist (IL1ra) 67, Na+, K+-ATPase (ATP1A2), potassium channel alpha subunit KCNS19
and voltage gated calcium channel subunits CACNA1A23 and CACNA2D353. For a comprehensive review see Diatchenko and coworkers13. Because of interrelationships among several of these psychological variables,
which are associated with chronic pain conditions, it is expected several of the identified
genes will influence multiple psychological variables. As an example, it is known that,
common polymorphisms in the promoter of 5-HTT gene are associated with depressive
symptoms, diagnosable depression, suicidality in relation to stressful life events7, 41,
anxiety-related personality traits27, somatic awareness, and the development of TMD34.

I think most of these may be common traits in hypermobility disorders too. The new diagnostic categories for EDS include one that is something like 'historic EDS' where associated problem emerge later in life, but it doesn't explain the whys. It's possible one could substitute 'hypermobility EDS' for TMD in 'The same psychological characteristics are
hypothesized to be intermediate phenotypes for TMD.' But it wouldn't have to take full blown clinical symtoms to trigger the connective tissue weakness, just having the genetic propensity for both.

It's late and I have no idea if I'm making sense, so signing off!

[ACK025]

Hello
I have just joined the group after doing a Google search for APOE4 and Ehlers. Posts from this group came up in results.

I too have Ehlers-Danlos (hEDS). Genetist clinically diagnosed. Also features of Marfan.
Other family members have features but I am the only one diagnosed as of yet.
I too am the first to find out I carry the APOE4.

Just wanted to say thank you for the information in the thread. And let you know I too have connective tissue disorder (with symptoms) and the APOE4 confirmed (with the beginnings of cognitive impairment currently being further evaluated and soon to begin Namenda).

*Lyme Disease also 3 decades ago (treated with extended courses of antibiotics and treated for 2 other related infections).

[floramaria]

Hello
I have just joined the group after doing a Google search for APOE4 and Ehlers. Posts from this group came up in results.

I too have Ehlers-Danlos (hEDS). Genetist clinically diagnosed. Also features of Marfan.
Other family members have features but I am the only one diagnosed as of yet.
I too am the first to find out I carry the APOE4.

Just wanted to say thank you for the information in the thread. And let you know I too have connective tissue disorder (with symptoms) and the APOE4 confirmed (with the beginnings of cognitive impairment currently being further evaluated and soon to begin Namenda).

*Lyme Disease also 3 decades ago (treated with extended courses of antibiotics and treated for 2 other related infections).

Welcome ACK025!

Thank you for joining us and sharing your experience. I am happy to know that you appreciated the information in the thread. If you are interested in seeing more posts on the site related to Ehlers-Danlos, you can type Ehler-Danlos into the Search function , which you access with the magnifying glass to the left of your user name. I just tried that and it turned up 37 matches, only some of which were in this thread. You might search for other terms that are relevant to you as well.

For a broad overview of the implications of ApoE4 allele the primary interventions to reduce associated risk, the Primer is a tremendous resource. It is written and regularly updated by a physician member. We also have a Wiki contains a lot of information, including a section that offers tips on getting the most out of the website.

This is a lively and welcoming community where information, personal experience, and support are shared. We welcome you and invite you to participate. To share more about yourself, the thread Our Stories is a good place to add to your introduction.