1. Why the presence of genes means nothing to disease risk.
2. What do people over 100 years old teach us about genetics?
3. What six pieces of evidence found in 2011 tell us about AD or PD etiology?
4. How will industry try to solve the mystery?
5. What you can do right now to obliterate your current risk of AD and PD?
If you did not know that Ronald Reagan suffered and died from end stage Alzheimer’s, you do now. Micheal J. Fox is afflicted with Parkinson’s disease and trying to solve its etiology as a fundraiser. Recently in 2011, several announcements were made that several genetic mutations seem to predispose us to Alzheimer’s disease (AD) and Parkinson’s Disease (PD). I tend to glance over these findings often because based upon my current understanding, genetic mutations are not where science seems to be headed these days. Genetic determinism has been the dogma for the last 50 years, but the most recent data suggest that we can reprogram our genes by turning on and off their function if we know how. This makes sense considering that most biologic systems don’t rely on the presence or absence of genes in disease states. In fact, in Mount Sinai’s supercentenarian group they found that the longest lived people all tend to have the “bad genes” in their cells we all worry about. The interesting part is that they are not “turned on” and appear to be of no consequence to those people.
The old dogma led us to believe that the mere presence of these genes spelled doom. If you don’t think genetic determinism is alive and well in 2011, talk to any woman who tests positive for the BRCA 1 gene for breast cancer. Many of these women are electing for mastectomies in the face of no immediate cancer presence just because of the scare due to the BRCA 1 gene being present. I don’t advocate that kind of thinking. WHY? The Mount Sinai supercentenary group makes a great example for us to learn from. Think of an analogy of genes and their epigenetic signals to a “stick of dynamite” and “lit match”. A stick of dynamite is not dangerous to us unless it is around a lit match. It appears the same is true for genes. The mere presence means little as long as the on switch is not present at the same time. This is where genetic testing is now headed.
The recent AD announcements gained lots of attention but the thing that caught my eye about the genes found in AD patients were all tied to lipid metabolism and inflammation generation. The AD jigsaw puzzle is a long way from complete, but pieces are emerging that suggest inflammation is the root cause of this condition. So Dr. Kruse, what exactly are those pieces of evidence? What six things have we learned about the brain and neurodegenerative disorders as of 2011?
1. The genesis cause of AD et al is caused by the presence of insoluble plaques made up of a protein called Amyloid beta (A-beta) inside neurons.
These proteins block signal transmission and molecule transfers that occur in the brain normally. This process continues for sometime and then another protein becomes more common called Tau protein. When both occur together they begin to interact and form the insoluble protein called a neurofibrillary tangle that is classically associated with many neurodegenerative diseases. (AD, Parkinson’s, and Mad Cow disease are a few)
2. The second bit of evidence is found on the APO E gene present on chromosome 19. If it is present, many researchers and clinicians believe your risk of getting AD rises. In fact, having two copies of the many we have of this gene, raises your risk of developing AD 20-fold before the age of 75! So APO E presence sounds bad does it not?
Guess what APO E gene function is for? It is to remove the build up of the A-beta and Tau proteins before they induce nerve damage and eventual cell suicide. The solubility factor is important because it is determined by how the protein folds after it is made. If it folds incorrectly it become less soluble. This is why we can see these tangles under a microscope. So this means that the presence of APO E gene is a great thing and not a bad thing that many have been led to believe the last 15 years. More proof that genetic determinism is not as important as the epigenomic effects upon those genes.
3. The third bit of evidence comes from Dr Chris Dobson’s lab in Cambridge University.
He cleverly made 17 small genetic adjustments to the A-beta protein in the lab to make it either more or less soluble. After doing this he then transferred these genetically altered proteins into the DNA of fruit flies and clearly proved that the less soluble the protein transferred the shorter lived were the flies. Their life spans clearly correlated with the percent solubility of the protein transferred to the mutant flies. So after his experiment neuroscientists began to ask why do misfolded proteins show up in elderly brains to begin with?
4. It appears that all neurons have an internal quality control mechanism that not only detects misfolded proteins, but one that also self corrects this process from happening.
Research was published in March of 2011 from Brown University that both parts of this mechanism, the detector and refolder, are functional but overwhelmed in diseased brains with neurodegenerative changes. They can not keep up with the workload of all the A- beta protein being made.
5. Then the 5th bit of evidence came in April of 2011 from Dr. Jeffrey Kelly.
Dr Kelly is at the Scripps Research Institute, and found that a chemical formed when cholesterol reacts with ozone attaches to A-beta and makes misfolding hundreds of times more likely. Take a guess where Dr. Kelly found the ozone came from? It comes from inflammation generated within the neurons from cellular metabolism. This linked the etiology of protein misfolding directly to carbohydrate and omega six fuels in our diet and their eventual metabolism over years. Both of these pathways are known to cause the development of inflammation in human biochemistry. It also links diabetes risk to AD fairly tightly. This news is not surprising to my readers at all if you follow the Quilt’s Levees.
6. The last bit of evidence comes from the recent studies on studies on stress and the development of all neurodegenerative diseases. That is the hormone cortisol. This links another levee to the “brick in the wall.”
This is a clearly a hormone most of my blog readers have become quite familiar with. Remember that cortisol rises in end-stage leptin resistance to cause the generation of even more inflammatory cytokines. Remember that cortisol is made from the cholesterol backbone, pregnenolone. 2011 work done at the University of California at Irvine has pointed to the elevation of cortisol as the main generator of the inflammation in diseased neurons. This further fuels protein misfolding and overwhelms the detector and refolding mechanisms in the brain.
It appears that the brains cholesterol stores are used up to make the cortisol that fuels the inflammation that drives this pathologic process. This inflammation becomes the currency that overwhelms the internal quality assurance system of neurons to make sure proper protein folding occurs. When the system is overwhelmed the end result is the formation of neurofibrillary tangles from insoluble proteins. These insoluble proteins then block the transport of vital ingredients into the brain cells to offset the assault. One of those ingredients appears to be cholesterol itself. It appears that normal lipid metabolism repair mechanisms become so unbalanced that it induces the nerve cells to undergo apoptosis! This ties another levee to the AD and Parkinson’s disease story.
Many physicians and researchers are hoping that we can find a place in this chain of events that can be attacked or blocked by a medication to prevent the inflammation, production of ozone reactions, slow the conversion of cholesterol to cortisol, and encourage the refolding apparatus that evolution provided us to make a dent in this disease. Maybe then we can improve protein solubility and even boost the plaque removal mechanism that we were born with? I have a better idea. Why don’t we stop providing that the fuels that are known to provide the ” lit match” to the dynamite?
Maybe we should advocate a low carb paleolithic diet that decreases carbohydrates that upregulate IGF 1 and 2 and lower omega six free fatty acids? We know that will help slow the progression of the disease since we now know what drives it. Some how I bet they’d rather make a drug they could make money on then teach people what really might help now? After all, no food company makes money unless they are selling the SAD do they. The choice is clearly yours to ponder.
Thank you for posting this! I have a blog devoted to showing the connections between eating high carb and AD and PD.
Awesome……put a link here so others can read it.
@ Sandy regarding your email to me…….A point to be clear. While many report a decrease in DHA in the brains of AD patients we should not advocate a high 03 supplementation with marine fish oil for this disease. I think it is great to eat omega three's from whole foods and in Neurodegenerative disease in general but supplementing them could lead to problem in AD. Remember in AD we are actively breaking down fats to make cortisol. This is a form of pregnenlone steal. So when we break down the FFA in cell membranes many PUFA's are liberated. DHA/EPA is a PUFA. It is also very susceptible to oxidation and inflammation production through its metabolites when it is broken down. This is where ozone and NO come from. The products of PUFA decomposition include ethane, acroleins, malondialdehyde (MDH), Pentanes, crotonaldehydes, and neuroprostanes (NP). The NP are chemicals which are PG like compounds formed from the metabolism of DHA. Since the brain is deficient in fats in AD due to the pregnenlone steal syndrome we need to replace the fat with saturated fats not PUFA's! My favorite fat replacement for AD diets by far is coconut oil. I'm wary of the the reactive fats species formed from lipid peroxidation of DHA and EPA supplements in AD.
So, in otherwise healthy individuals, Is supplementation with fish oil OK? When these oils are metabolized, would they not oxidize into the same byproducts that would enable the plaque proteins etc.? And what about supplementation for those with borderline AD or PD, i.e. not yet diagnosed?
What are your thoughts?
Hi Jack. Another thoughtful post. Stephanie Seneff at MIT has proposed a mechanism where carbs are to blame for Alzheimer's. You may find her theory (and mechanism) interesting, and it may complement your take. Let me know what you think. Thanks.
Dr. Harris warns against fish oil supplementation; my doctor disagrees, prescribing supplementation until the 6:3 ratio has been corrected. I too would be interested in Dr. Kruse's views on this.
A hunter-gatherer or Paleolithic human might have had a total PUFA intake of 3% of calories. Modern north americans have a PUFA intake of around 15%, most of it due to n-6. The problem with this is twofold.
1) As n-3 and n-6 precursors compete for the same enzyme in the eicosanoid pathway, the excess of n-6 in the diet means that n-3 is outcompeted at the enzyme level. The result is a preponderance of inflammatory molecules. Increased cancer and inflammation are both likely related to this
2) Many are aware that 6:3 ratio is important, so they try to compensate by taking fish oil to balance the 6:3 ratio. This doesn't really work too well – you can't realistically eat that much fish, and if you take fish oil supplements, you now exacerbate the second and more important problem with excess n-6, which is your total PUFA intake. High total PUFA, especially including the highly unstable n-3, leads to oxidative damage to your cells. Your arteries, liver and other organs don't appreciate extra oxidative damage.
The way to correct the modern excess of n-6 or linoleic acid is to avoid the modern sources of it. Stop eating all temperate vegetable oils – cooking and frying oils like corn, soy, canola, flax, all of it. And go easy on the nuts and factory chicken. These are big sources of n-6, especially the nuts and nut oils.
I really like the dyanmite and match analogy for activating gene expression. It makes sense that our body would turn signals on and off according to outside stimulus.
Thank you! Dr. Kruse, what would be your recommendation for folks who have difficulty obtaining pastured or wild meats? Should they go for the lower fat choices (like skinless chicken breasts) and add coconut oil?
I was wondering if there is anywhere with details on Michael J. Fox's diet or Ronald Reagan's diet. I'm also wondering if changing diet could help those already afflicted like Michael J. Fox(possibly cure?) I would think if there were anything as simple as a diet change that could have fixed things for him he would have already found out….
There is the case of Dr Mary Newport's husband, Steve Newport, who is suffering AD. She started advocating use of coconut oil when Steve was able to reverse some of the symptoms of AD three years ago. Now it appears her focus is more on ketosis as perhaps being the path to finding a cure. Is it the ketosis or is it the saturated fat in coconut oil or a combination? And, are we seeing an increasing rate of AD due to the last forty yearas of the campaign against arterycloggingsaturatedfat?
Thanks, Jack! Here is the link to my Alzheimer's blog:
If you click "Like" it will get out to more people via Facebook accounts.
@ Resurg…..I like 03 supplements but in neurodegenerative diseases I am rather cautious with the use of them for the reasons stated.
@ Dex……Im a aware of this site. Coconut oil is critical
@Jon I have no idea what he eats but at one time it was not good.
@CGB….KGH maybe correct about 03 in some cases but not all. I think if our ratios our bad we need Rx grade supplements. However in Neurodegenrative disease I am not a fan of 03 supplementation. I want you eating o3 from whole foods instead. Not all disease call for the same treatments. If you read my post in august right before AHS 2011 I go into why Fish oil as advocated by Robb Wolf in his book is a bad idea…….Not everything Dr. Harris or Robb say are correct and in this case I disagree with both. Neurodegeneration is an area I think I have a pretty good handle on the current research. Read Patricia Kane’s work at Hopkins because it shoots Harris and Wolf in the heart.
@poison…..well aware of her work. But I think she has only part of the story locked in.
At several replies: There are two types of Alzheimer'sâ€”early-onset and late-onset. Both types have a genetic components. Early-onset Alzheimer's disease occurs in people age 30 to 60. It is rare, representing less than 5 percent of all people who have Alzheimer's. Some cases of early-onset Alzheimer's have no known cause, but most cases are inherited, a type known as familial Alzheimer's disease. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2. Late onset AD oocurs by a different method. This increased risk is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE contains the instructions for making a protein that helps carry cholesterol and other types of fat in the bloodstream. APOE comes in several different forms, or alleles. Three formsâ€”APOE Îµ2, APOE Îµ3, and APOE Îµ4â€”occur most frequently.
APOE Îµ2 is relatively rare and may provide some protection against the disease. If Alzheimer's disease occurs in a person with this allele, it develops later in life than it would in someone with the APOE Îµ4 gene.
APOE Îµ3, the most common allele, is believed to play a neutral role in the diseaseâ€”neither decreasing nor increasing risk.
APOE Îµ4 is present in about 25 to 30 percent of the population and in about 40 percent of all people with late-onset Alzheimer's. People who develop Alzheimer's are more likely to have an APOE Îµ4 allele than people who do not develop the disease. Dozens of studies have confirmed that the APOE Îµ4 allele increases the risk of developing Alzheimer's, but how that happens is not yet understood. From my blog you now should get how that happens.
Scientists have long thought that genetic and environmental factors interact to influence a person's biological makeup, including the predisposition to different diseases. More recently, they have discovered the biological mechanisms for those interactions. The expression of genes (when particular genes are "switched" on or off) can be affectedâ€”positively and negativelyâ€”by environmental factors, such as exercise, diet, chemicals, or smoking, to which an individual may be exposed, even in the womb.
Epigenetics is an emerging frontier of science focused on how and when particular genes are expressed. It appears genes are not the critical factor in disease presence in AD. Diet and exposure to chemicals in the environment, among other factors, throughout all stages of life can alter a cell's DNA in ways that affect the activity of genes. That can make people more or less susceptible to developing a disease later in life. There is some emerging evidence that epigenetic mechanisms contribute to Alzheimer's disease. Epigenetic changes, whether protective, benign, or harmful, may help explain, for example, why one family member develops the disease and another does not. Research supported by the National Institutes of Health continues to explore this avenue.
Read this thesis on the APO E 4 allele for a full up to date version .http://www.kliniskbiokemi.net/pdfiler/DisputatsElektronisk.pdf
Isn't cortisol responsible for anti-inflamatory effect ?
@Maj. Acutely it is but long term it is a potent immunosuppressant and reduces natural killer lymphocytes tremendously. The diseases mentioned above are all chronic as is ibesity. Anything chronically elevating cortisol or insulin long enough will eventually kill you because it slowly detroys your immune system
Have you seen this article?
@ Ray yes I have. It completely falls in line with my Alzheimer's posts and my series on concussions.
Could u comment on FTD or frontotemporal dementia.?
Is there a way to reverse the process in the brain through diet …? What might that diet be?
@Brenner FTD is a classic neurodegenerative disorder and I wrote about it in my CTE series on the blog. Bob Mackey the great Colts TE died from it and I believe it was tied to his concussion history and his use of excitotoxins that escalated its damage.
Trying to tie the red thread through your post and the referenced work of Seneff, wherein she notes that aBeta may be evidence of a failed repair mechanism. It feels like the nub may be in the Q/A from/to @majkinetor, as it was also my understanding that a primary function of cortisol was to reduce, not 'fuel', inflammation, wherein you acknowledge that cortisol has an acute role in reducing inflammation.
Could it be that when the brain is inflamed (e.g. induced by carbs/PUFA), it consumes local cholesterol (from glial cells/myelin) as source material to make cortisol to acutely fight that inflammation? As this escalates, the brain makes aB to make up for insufficient cholesterol (ref: Seneff), but once 'overwhelmed' – a state reched more easily for those with APOE4's because they can't clear the surplus materials as well – the garbage accumulates (like the residue from exploded dynamite)?
The general remedy to stop initial inflammation would be the same (i.e. don't eat carbs/PUFA's), but a corollary might explain the logic why an APOE4 carrier ought to maintain *higher* cholesterol levels to better repair the inflammation when and where it does occur?
Does this make sense?
PS: Merry Christmas to you and your family!
@Russ acute cortisol release is very anti inflammatory but chronic release causes the exact opposite problem. This is another example of the pleiotrophic action of a hormone. You need to understand the context of how and when it is working to understand the effects.
Jack, Thanks. Fascinating. I have much to learn yet. Pleiotrophy sounds like something to put on the learning list – very clear how in this case it could lead to a terribly vicious cycle. Will read on…
I was looking at another of your forums, and you mentioned a d3 deficiency with scoliosis and leaky gut. My daughter was diagnosed with scholiosis and had headaches in her early teens. She went to Brazil for two summers and each she got home she swore she was well in Brazil and got sick and felt bad in the US. I thought she was silly. She was later diagnosed with bipolar and had anorexia prior to each episode. Now we are learning about leaky gut and in fact the bread in Brazil is a yucca bread, she also ate rice while there and tons of coconut milk. Each time she was hospitalized she would say if I let her go to Brazil she would get better. I am sure the leaky gut/leaky brain is the problem, now that I am learning about cytokines. I read that the water soluble vitamins leak out of the Blood Brain Barrier. Is there any practical way to supplement and get the vitamins back in? Also, is there a test for ok cytokines and a way of knowing if the barrier is healed?
@Lee Your daughter found out that her diet controlled her scoliosis……and she has tapped on information that I also believe now as a spine surgeon. The real problem is most spine surgeons do not know this yet.
Please take my last name down
I'm new to this blog and most seems way over my head, but I believe I need to change my diet. I've had a terrible bladder disease, interstitial cystitis for 40 years and I believe my nervous system has changed so that I am more pain sensitive. My memory and processing is going down the tubes,too. I need to save my mind at least so I'm going to try to get away from sugar and so much grains ( I've been 20 pounds overweight and I have lost 10). It is hard to do this around people who take great joy in eating a variety of cultural food and are not particularily fat. (I think of my little aunt who at 96 has her health and eats small amounts of whatever, but expells all her angst in wild outbursts never worrying about tomorrow.) Meanwhile I just suffer and worry and analyze and have a hard time complying, but I need to change.
@Susan If youre ready for change youre in the correct spot. If one changes endogenously……… one should not continue to live with the same internal thoughts of yesterday. They reflect one's mind and the psyche of your yesterday's………….when you are trying to get to your optimal tomorrow. Something more for you to ponder this AM as the sun rises.
Read this……. .https://jackkruse.com/finding-your-primal-sense/
I have often wondered if my father's onset of PD is the result of his antidepressant. I think it was called Abilify…Could changing his diet help him get better?
@Debi changing his diet would be a very smart thing to do. I am not a fan of antidepressants for PD
Dr Kruse, wonderful information on your site. Am working with cortisol/pregnenalone supplementation through a holistic practitioner due to low cortisol (late stage 2) and for past year eating a low carb/paleo-like diet. Significant improvements in health, but still having concerns with candida and it’s effects, despite many strategies to correct (fasting, supervised Rx quality supplementation, etc). How do you work with those issues or recommend tackling the issue?
I’ve had rheumatoid arthritis since age 3 (35 years) and just found out I’m ApoE 4/4 🙁 Since eating a higher (good) fat / lower carb / wheat & dairy free diet, my HDL has finally gone up to 68 and my triglycerides are 48, but m LDL (130’s) and total cholesterol (225) have both increased.
Just wondering whether to go NO carb (except veggies – no roots) and increase m good fats, or stay with mainstream medicine (yikes!) and go lowfat/lo-cal. I don’t want dementia when I’m 40! Your input would be MOST appreciated! Thanks for all you do!
I am an overall healthy male in his early twenties who has been on a paleo diet since last november. Since age 15 whenever it is hot outside and I go out in the sun and my body warms up I begin to get itchy all over and I start to get hives. Usually getting out of the sun or cooling myself off can prevent the hives from developing, but I still get the itchy sensation that goes away pretty quickly. This also happens, but I actually get hives, when something embarrassing happens and my body warms up that way. Sometimes it is too uncomfortable to even watch a funny recording of friends because this condition seems to be triggered by some emotional response causing my body to heat up. Any ideas?
I was diagnosed 2 years ago at age 63. Symptoms were a tremor in the right leg, loss of handwriting ability, and soft voice. I also have difficulty rising from a seated position and have balance issues. I started out taking only Azilect, then Mirapex, and 6 months ago Sinemet. Several months ago I started falling frequently, hence the reason for Sinemet. I tried every shot available but nothing worked. In June 2018, my neurologist and I decided to go with natural treatment and was introduced to chronotherapy. I had a total decline of symptoms with this treatment, the Tremor, falling frequently, stiffness, body weakness, balance issues, depression, and others have subsided. This treatment is a breakthrough for all suffering from Parkinson’s, don’t give up Hope. Thanks Jack