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By Meleni Aldridge
Executive Coordinator, ANH-Intl
Human physiology has developed robust reactions that aim to ensure survival of the species. But these robust reactions are not always beneficial to the body, producing diseases and disease consequences as a result. From the perspective of evolutionary medicine, it is becoming increasingly apparent that Alzheimer's disease (AD) is one such robust reaction — a non-permissive brain disorder, or human hibernation reaction, as a last ditch strategy to survive and protect against potentially fatal immunological and metabolic danger. Owing to their fundamental nature, the metabolic and immune systems were among the first systems to evolve in living creatures. This has made them somewhat symbiotic and inseparable when responding to challenge. Successful approaches to treating the cause of disease must therefore address potential imbalances in both.
Partial pieces of the Alzheimer's puzzle?
It's 2013 and if nothing else, we can be sure of three things. Firstly, chronic inflammatory diseases (CID) are rising in frequency, but successful treatment is still in its infancy. Secondly, many of the chronic diseases that plague the modern industrialised world never existed 200 years ago, albeit we live on average somewhat longer. And, thirdly, despite the obscene sums of money changing hands in healthcare, conventional medicine is doing precious little to address the real origins of these diseases. Evolutionary selection pressure has shaped human physiology to survive and reproduce, promoting direct survival over reproduction. Yet very few heads seem to be turned towards evolutionary medicine as a means to understand CID and the systemic consequences of a chronically activated immune system.
A new study, being hailed by many as a major breakthrough in the treatment of AD, centres on B vitamins. Participants took 20 mg B6, 500 mcg B12 and 800 mcg folic acid, then 168 out of the total 271 received brain scans. There's no denying that the results were hugely significant. Those taking the B vitamins had around half the amount of brain shrinkage associated with AD as against those taking the placebo. But is this really the whole story?
Well-known UK nutritional practitioner and author, Patrick Holford says, triumphantly, "The bottom line is that we can prevent half of all cases of Alzheimer's disease, saving billions, based on the evidence to date. This shows that, in those with blood homocysteine levels above 10 μmol/L (that's almost half of all people above 60) giving high dose B vitamins (B6 20mg, B12 500mcg, folic acid 800mcg) effectively stops both the accelerated brain shrinkage and memory loss, which are the two hallmarks of Alzheimer's. In an enlightened world we would screen for cognitive function from age 50, test for homocysteine if results not great, then prescribe B vitamins. That's why we set up the free on-line Cognitive Function test at www.foodforthebrain.org." He goes on to say, "It is extraordinary to think that, not only is all this evidence being ignored and side-lined, but EU laws actually threaten to outlaw the very supplements that we would need to prevent Alzheimer's."
But are these essential vitamins treating the symptoms or the cause?
Whilst B vitamins are hugely important for energy metabolism and keeping homocysteine levels in check, are they really the solution to preventing AD rather than managing its symptoms? Looking through an evolutionary medicine lens, the answer is probably no. The experience of the participant who spoke of his supplement holiday only to suffer a return of his symptoms would attest to their amelioration effect certainly, but B vitamins alone are clearly not addressing the cause. It's also important to note that only those with high homocysteine levels (over 13 μmol/L, normal parameters being around 7-10 μmol/L) benefited from taking such doses of B vitamins, and the study failed to answer the important question about whether brain shrinkage actually causes you to lose your memory.
Disposable organs
Our regulatory mechanisms (neuroendocrine and immune systems) evolved to cope with short life-threatening challenges such as sepsis or wound healing, and short non-life-threatening episodes. But not to deal with the persistent chronic activation we see today. The use of old survival mechanisms to deal with modern challenges results in CID symptoms that are 'borrowed' from the way we have always dealt with inflammatory challenges throughout our evolution. This means simply that our survival reaction to financial and emotional stress, sickness and obesity, for instance, is the same now as it was when we were running from or fighting off a sabre-toothed tiger. It's just that when we survived the tiger, it was over, and the immune and neuroendocrine systems stood down allowing normal homeostasis to return.
In today's world, the stress is persistent, leading to chronic activation of the immune system, which diverts a huge amount of resources to assuage the heavy energy demand. In some clinical circles, this has earned it the term, 'the selfish immune system'. Having moved from normal homeostasis where the 'selfish brain' is 'king' with first dibs on energy resources, the selfish immune system now takes over. Organs and tissues not involved in direct survival are downgraded to only the most basic of functions and all available energy is diverted to the energy-expensive immune system. Creating what we recognise as sickness behaviour. This is all perfectly normal and healthy when it occurs for a very short period of time, but extended over weeks, months or years, creates a situation where organs are 'disposed' of in an attempt to protect against multiple organ failure as there just isn’t enough energy to go round.
Biological priorities and the brain
Brain function, blood circulation and anatomy are disturbed in patients with CID, such as AD, Parkinson's disease, fibromyalgia, depression and chronic fatigue syndrome. Whilst it's always been thought that the brain remains 'king' no matter which other organs are disposed of, these symptoms point to the selfish brain being deposed and overridden by another system — the hugely energy expensive immune system.
During evolution, long-term involvement of the central nervous system in stressful situations has been rare and it may be that the occurrence of these brain diseases can only be explained by the presence of danger signals that remain unsolved or register as unsolvable. So whilst no one would ever choose to develop AD or any other brain disease, from an evolutionary perspective, it may be the involuntary choice to ensure survival. A robust reaction to cope with a low metabolic energetic state arising from chronic inflammation and persistent activation of the immune system rather than dying from multiple organ failure.
Inflammation is lifesaving when controlled and lasting for a short duration, but deadly when not. Danger appears to put the immune system on top in hierarchy, which overrides the 'selfish brain'. Persistent inflammation is considered dangerous to survival, and persistent inflammation that lasts over years, even decades, may be registered as an unsolvable danger. Energy conflicts and danger share the same phenomena during evolution. Therefore, exposure to chronic or multiple dangers should be considered the universal way of developing disease.
Energy conflicts leading to metabolic hibernation
The longer inflammation lasts the more organs and substances are co-opted by the immune system. Chronic stress and low-grade inflammation can become immune suppressive, which in itself can be protective to prevent further damage. It's been found that AD patients show a higher body temperature but low brain metabolism and temperature, as you would expect when the body is inflamed, but the brain 'disposed' of. On the contrary, healthy older people demonstrate lower body temperature and energy saving strategies like slightly lower metabolism, but normal brain function. The same strategy used in all mammals and humans during calorie restriction.
Whilst humans can't truly hibernate in the strict sense of the word, a number of parallels can be drawn. During the reduced physiological activity of torpor, animals show Alzheimer-anatomy. But unlike humans, these changes disappear 72 hours after emerging. Persistent low-grade inflammation can produce a metabolically-induced hibernation through reduced activity of the thyroid gland in order to conserve energy to divert to the immune system. Is it possible then that AD develops because of an evolutionary conserved mammalian hibernation response that causes a low brain metabolic rate in order to put the immune system at rest? In this way, the pathways leading to AD, whilst pathological, are actually protective.
Internationally acclaimed clinical psychoneuroimmunologist, Leo Pruimboom, concurs saying, "Several genes and their proteins associated with increased Alzheimer's disease susceptibility, also have pro-inflammatory functions providing protection against infection". He elucidates further, saying, "The high number of pathogenic microbes in the brain of Alzheimer’s disease patients can only be explained when individuals have been challenged by these microbes during decades, perhaps because of increased permeability of the gut and the mouth barrier as evidenced by the presence of antibodies against oral bacteria in patients suffering from Alzheimer’s disease. It is conceivable that the person suffering from Alzheimer’s disease reached the age of clinical symptomatology because of his/her highly effective pro-inflammatory functioning immune system. This activity protects the person against infection but at the price of slow neurodegeneration".
Downstream prevention, upstream effects
The real causes of AD, like so many other diseases, are decades downstream from the evidence of the first symptoms. Yet there is still no real attempt at preventative healthcare or education about the hugely deleterious effects of persistent, chronic, low-grade inflammation. If evolutionary medicine is on the right track with regards AD, then the answers surely lie in the symbiotic and inseparable relationship of the immune and metabolic systems rather than throwing good money after bad in expensive upstream drug trials?
With the evidence from the B vitamin study offering promising support for AD patients, medical journalist, Jerome Burne, draws our attention to the unpalatable reality of modern healthcare. Despite the proof that cheap-as-chips, no side-effects, B vitamins can slow down brain shrinkage, a £2 million drug trial on blood pressure drug Losartan is due to start later this year to explore exactly the same effects!
As conventional medical science seems to descend ever further into pantomime, maybe it's time we all shouted in unison, "it's behind you"! This time it really is – way downstream.
Comments
your voice counts
30 May 2013 at 7:58 pm
The link between sustained stress levels and Alzheimer's disease appears to be supported by researchers from the University of Pittsburgh who spent several years studying over-55s in Ballabgarh in northern India, an area which has unusually low levels of Alzheimer's disease - read more http://news.bbc.co.uk/1/hi/health/8492918.stm.
My sister was diagnosed with Bi-polar disease and I have suffered with a degree of it. My part solution was to successfully supplement with ashwagandha and a brahmi formula. Ashwagandha gently alleviates stress and Brahmi protects and promotes healthy brain function. Both of these Ayurvedic remedies are being suppressed by the EU Commission, yet these and other botanical remedies have huge potential in easing and curbing the ill effects of western lifestyle, in tandem with healthy diet and exercise.
Recommended reading on this topic is "Brain Longevity" by Dharma Singh Khalsa M.D. with Cameron Stauth. Andrew Weil M.D. says it is "A must read for everyone interested in defending themselves against age-related loss of memory and other mental functions. Dr. Khalsa is currently engaged in a study at the University of California, Los Angeles (UCLA), in conjunction with the Department of Psychiatry, aimed at reducing stress response and improving cognitive functioning in older family dementia caregivers.
01 June 2013 at 2:06 pm
Vitamins B6, folic acid and B12 were found to treat raised cholesterol - another inflammatory process linked to homocysteine. The scientist who discovered this was destroyed by the pharmaceutical company who first introduced statins. By discrediting him they were able to make billions out of a drug with wide side effects and increased morbity/mortablity. A safe way of treating a range of disease caused by inflammatory processes was discredited and so never made available to us. The pharmaceutical industry are the pits.
01 June 2013 at 2:52 pm
I monitor mainstream medical and biosciences journals for many decades. I also took care of many hospitalized patients who manifested strong signs of dementia. In addition to regular blood chemistries, patient were tested for vitamin B12 deficiency and homocysteine levels – in order not to overlook any easily correctable problem.
Observations:
1. We observed that ALL patients with dementia had low or low-normal levels (less than 400 pg/mL) of vitamin B12 and high or high-normal levels of homocysteine. These findings were very disturbing to me, as I was aware of the fact that about five to ten percent of people with vitamin B12 levels in 211 to 400 pg/mL range already have some neurological or psychological problems. I was also aware that many countries established much higher minimum vitamin B12 levels than ours. Optimal levels of vitamin B12 are 550 pg/mL and above. This is almost three times as high as current U.S. mediocre minimum of 211 pg/mL. Actually, the higher the level, the better.
2. Active, methylcobalamin form of vitamin B12 is much better choice, as some people are not able to convert cyanocobalamin into active, methylcobalamin form. Additionally, older people often have their ability to absorb adequate amounts of vitamin B12 severely compromised due to decrease in stomach acid production or use of some over-the counter or prescription medications.
3. Magnetic Resonance Imaging (MRI) scans of brains of patients with memory problems frequently demonstrate damage of small blood vessels that supply white matter of brain with nutrients and oxygen and damage or atrophy of white matter and brain volume loss "consistent with patient's age."
4. Primates, however, don't shrink their brains as they age. Primates living in the wild also never develop heart disease, but they do in zoo. Plausible explanation? Primates don't know (yet) how to start the fire and for this reason can't cook their food. Cooking destroys vitamin C, folic acid, other vitamins, and many nutrients and enzymes that are present in raw food. By not cooking food, primates maintain optimal (high) intake of vitamin C, Folic acid, vitamin K, calcium, magnesium, and many other nutrients essential in maintaining good collagen synthesis and good quality of their blood vessels. Collagen (elastin) makes blood vessel walls strong, skin elastic, and bones more resilient and less likely to break due to improved quality of collagen matrix of bones.
5. Aging in Greece? Very old Greeks were called Greek philosophers. Their diet was, and still is, fresh seafood (best source of vitamin B12 and fish oil, both are brain-friendly), salads (good source of vitamin C, folic acid, vitamin K, fiber, essential minerals and essential sugars) and a lot of olive oil, a brain- and blood vessel-friendly fat. Plenty of sunshine provides them with plenty of vitamin D. Mediterranean diet is associated with extremely low incidence of cardiovascular disease. Just Google "salad nicoise" to find thousands of recipes for delicious Mediterranean dishes.
6. Aging in India? Dementia in India is rare. Plausible explanation? Plenty of onions and other vegetables is the culinary rule. Plenty of turmeric assures relaxation of small blood vessel walls and thus better perfusion of brain and toes. Turmeric is also known for its anti-inflammatory, anti-bacterial, anti-fungal and anti-viral properties. It is a staple food (spice) of India and Thai cuisine.
7. See your doctor for general medical care. Your doctor will be very helpful with providing preventive medical care and may also be willing to check if your vitamin B12 level is optimal. Ask for it. Our experience is that patients who follow Asian or Modified Mediterranean diet (consume fish, but avoid other meats) and suffer no nutritional deficiencies do well, stay smart, are more active, and march towards 100, with three passing that mark.
16 June 2013 at 9:39 am
There is one fundamental error and one misconception in your article on Alzheimer’s.
The first is that the level of homocysteine above which brain shrinkage is likely to be occurring is 9.5mcmol/l, not 13. This is important because probable one on two over 65 have a level of homocysteine above 13 and, consequent brain shrinkage, which can be arrested by supplementing B vitamins, according to Professor David’s Smith excellent research at Oxford University.
The second is the suggestion that homocysteine isn’t ‘causal’ in the development of Alzheimer’s, but perhaps just a marker.
Homocysteine is both a neurotoxin, damaging DNA and the neurons that are the hallmark of Alzheimer’s. As a consequence amyloid and tau protein accumulate. Homocysteine is also an indicator of disrupted methylation, and that also leads to raised rogue proteins that are central to how neurons get killed off. Probably the best review of all this is Zhuo et al ‘Is hyperhomocysteinemia an Alzheimer's disease (AD) risk factor, an AD marker, or neither? [http://www.ncbi.nlm.nih.gov/pubmed/21684021]
What is important about the recent research is that it shows that lowering homocysteine with high dose B6, folic acid and B12 in those with early signs of cognitive impairment, reduces the rate of brain shrinkage by more than eight times those on placebo, with parallel cessation of further memory decline. All this is fits perfectly with homocysteine, and disrupted methylation, being at the root cause of Alzheimers-related brain damage.
If you go further downstream and ask what is causing raised homocysteine there are many factors inherent in our ‘unnatural’ way of living and eating in the 21st century – smoking, stress, coffee, lack of exercise and so on. All these are associated with raised homocysteine.
But the strongest evidence by far exists for a lack of folic acid and B12. Folic acid intake has declined as a consequence of not eating the quantities of fresh plant food our ancestors would have. B12 insufficiency is more interesting. It does not appear to be so much a lack of dietary B12, but increasingly poor absorption of B12 with age. A study in the UK found that 2 in 5 people over age 61 had insufficient levels of B12 in their blood to stop brain shrinkage. The only currently known way to stop this is to either supplement much more than one could eat (the effective studies give 500mcg of B12, compared to the RDA of 2.5mcg) or inject it.
If you go one step further and ask ‘what is causing poor B12 absorption?’ a lack of stomach acid secretions, sometimes due to medical drugs (eg PPI antacids and the diabetes drug metformin), possibly a lack of zinc needed to make stomach acid, and so on.
But, whichever way you cut it lack of B vitamins and consequent raised homocysteine, are bang in the centre for Alzheimer’s causality. In the same way that scurvy is a consequence of lack of vitamin C we can say that Alzheimer’s related brain shrinkage is a consequence of lack of B12. Of course, there will be many other contributory causes but this is most certainly one. Preventing it will early screening using our free online cognitive function test at www.foodforthebrain.org, measuring homocysteine, and supplementing B vitamins in the right dose if required, is likely to prevent half of all cases of Alzheimer's and that's important for people to know.
Patrick Holford – Food for the Brain Foundation
See www.foodforthebrain.org/hcyevidence for a summary of research to date.
18 June 2013 at 11:43 am
Thank you for your comment and clarifications. But in the spirit of maintaining a healthy debate on these complex issues, we feel it's important to respond to what you feel is a misconception on our part regarding the causal implication of high homocysteine levels on Alzheimer's Disease (AD). While we all agree that around half of all patients presenting with AD have a high homocysteine level, that’s still only half of them! We were attempting to write a contemplative article that looks at the AD population as a whole and moves away from proximate medicine (a ‘pill for an ill’). Our emphasis was to look at some of the possible downstream and evolutionary mechanisms that might be involved in the AD epidemic more generally.
Evolutionary biologists have long maintained that in diseases that become common, there is likely to be some kind of evolutionary benefit associated with the metabolic pathway that leads to the disease. Whilst the disease is definitely not desirable, the mechanism leading to it may well be. Otherwise it is likely that the pathways themselves would have been selected out by evolution.
For example, if we hadn't mutated the uricase gene and lost the ability to make vitamin C, it's unlikely that humans would ever have been able to stand up (Watanabe 2002; Johnson 2008). But in the process we lost the ability to gradually reduce our uric acid and we're very sensitive to sodium (Mazzali 2010), the result being a higher risk of high blood pressure and cardiovascular disease. Blue eyes is a mutation that enabled Europeans to become lactase persistent, but whilst the gene for making lactose persists into adulthood, the risk for developing certain diseases e.g. osteoporosis (Campbell 2006; Lanou 2005), cancer (Outwater 1996; Voskuil 2005) and multiple sclerosis, is increased (Shrier 2008). Evolutionary selection pressure is aligned to survival, but not necessarily to health.
Alzheimer's, rheumatoid arthritis, irritable bowel syndrome and depression are all deleterious diseases, but it's unlikely that we would still suffer from them if the pathways leading to them didn't have a certain benefit to the host, i.e. survival. All we were saying in the article is that more research work needs to be focussed on the devolutionary aspect of disease progression, once a chronically upregulated immune system is exhausted. Hence the introduction of new terminology, the 'selfish metabolism', which takes over from the selfish immune system, having taken over from the normally selfish brain. Homocysteine is a major metabolic player and, whilst we don't yet know the exact mechanisms involved, it fits with the hypothesis that a raised homocysteine level may well have a benefit to the host in terms of survival, once the 'selfish metabolism' has taken over.
Additionally, it seems unlikely that there is yet sufficient evidence to know unequivocally whether high-dose B vitamins will prevent brain shrinkage over the rest of the life of the AD patient. And if this is sufficient to return their memory/cognitive function or halt any further deterioration. You probably have your hands on the most persuasive data in this regard, and we’d be only too happy to make them available in a subsequent piece.
17 August 2013 at 6:00 pm
A really useful article for discussing with people interested in the origin and prevention of cognitive decline, thank you. In the spirit of going 'downstream' (or should it be upstream?)further, does anyone have any comment on the impact of dysbiosis on endogenous B12 production, how relevant this might be in ageing population, and addressing this instead of using B supplements?
22 August 2013 at 1:09 pm
Thank you. It's a good point that you make - in that gut bacteria are important for endogenous B12 (and K) production. Therefore it follows that dysbiosis will impact B12 levels adversely. But the work of David Smith's group would suggest that the levels of B12, as well as those of folate and B6, required to reduce homocysteine are higher than those that can typically be achieved by normal diets and endogenous production alone, with older people being even more compromised in this respect than young ones. Perhaps one might speculate that if dysbiosis at an earlier age was prevented, the likelihood of neurodegenerative effects might be considerably reduced? As you'll know there is a good body of literature showing the pivotal role played by the gut microbiota and age-related chronic inflammation that underpins all major degenerative diseases (e.g. see review by Tayyab Rehman, Endocr Metab Immune Disord Drug Targets. 2012; 12(4): 361-7. Hope this is of some use.
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