because prevention is better than cure.

because prevention is better than cure.

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Amyloid isn’t Alzheimer’s – How NOT to Study a Disease

by Patrick Holford

If you think that Alzheimer’s or dementia is caused by amyloid plaques in the brain, or tangles of nerves (called neurofibrilliary tangles) associated with p-tau, you have been successfully deceived. =

But you would not be alone. Last week’s Telegraph article is a classic example of the spin. There is a vast sleight of hand going on that remarkably continues to hijack research into true causes and potential cures for Alzheimer’s despite a mountain of evidence to the contrary.

Let’s start at the beginning. Some people get increasingly severe cognitive decline. This affects about one in ten older people. We call this dementia. Some people with dementia, on scanning their brains, have big gaps in the central part of the brain, which is used to diagnose that dementia as Alzheimer’s disease due to the clear evidence of ‘pathology’ – something wrong in the brain that amounts to death of significant amounts of brain cells in critical areas. So, here we have two clear diagnostic criteria: Firstly, a loss of cognitive function which is what we test at foodforthebrain.org with our Cognitive Function test. Secondly, a loss of actual brain, which is diagnosed by a type of brain scan of the central or medial part of the brain which was first developed by the team at Oxford University, headed by Professor David Smith, a member of our Scientific Advisory Board.

What causes Alzheimer’s?

So, then the question is what causes it? There is no evidence, that it is caused by deposits of amyloid protein or amyloid plaque, in the brain. About 30% of older people have plaques in their brains without dementia.  About 15% of those with dementia don’t have amyloid plaques. Having amyloid plaques doesn’t cause dementia. Mice with amyloid plaques behave normally. Even a head full of plaques only results in mild memory problems. Many of us have plaques in our brain and remain completely healthy.

Even these associations are an exaggeration because it turned out that the presence of amyloid in brain scans was manipulated in key widely influential research leading to billions of dollars of research spend, exposed in the journal Science, in 2022, and subsequently retracted.

What happens if you ‘treat’ amyloid plaques? Blocking the enzymes that make amyloid have made people worse, not better, despite lessening the amyloid burden. Vaccinating animals to remove the plaques doesn’t change anything to do with dementia, but it does reduce the amyloid. The anti-amyloid vaccine injections in humans have been equally ineffective despite lowering the amyloid burden in the brains of those injected.

The pharmaceutical companies running these failed trials have pushed and pushed until they could just about get a significant difference in the rate of degeneration of patients versus placebo on questionnaires equivalent to less than half a point change on an 18 point scale. No-one got better. Quite a few got worse, with brain bleeding and swelling. A few died as a consequence. But still drug agencies, paid for by the drug industry, dished out licences. In the UK the watchdog NICE said the evidence wasn’t good enough and recommended the National Health Service not to give anti-amyloid treatment – at about £50,000 a patient per year.

 In scientific terms the trials added evidence to the mountain already existing that amyloid deposits don’t cause Alzheimer’s because lowering it doesn’t stop the disease process, doesn’t improve cognitive powers in any meaningful way and doesn’t slow down brain shrinkage. In fact, if anything, it accelerates the main physical measure of brain shrinkage. In the last anti-amyloid trial, donanemab, those on the amyloid treatment had considerably more brain shrinkage than those on the placebo.

You would think that the whole field would get the message by now, stop funding this dead end and explore other avenues. But they were so hoping and invested in the ‘amyloid cascade hypothesis’ that no-one could give up. It’s become an unhealthy obsession.

In the US the Alzheimer’s Association and in the UK the Alzheimer’s Society supported this line of thinking and continue to do so. ‘We are most proud of our contribution to amyloid’, declares the research director of the Alzheimer’s Society.

Why don’t they explore other avenues? It’s partly to do with money. No-one can get research money if they’re not looking at amyloid (or p-tau – more on this in a minute.)

In the UK the Medical Research Council continue to pour good money after bad by making another £20 million available for drug trials. That’s taxpayer’s money backing the wrong horse despite a lousy track record.  In the US the National Institutes of Health and the National Institutes of Aging spend vast sums pushing in this fruitless direction. Big pharma spend twice as much as the charities, funded by us taxpayers – probably around $150 billion so far. So, perhaps $250 billion has been spent getting almost nowhere. Sure, we know a lot more about amyloid and tau but are no closer to a ‘cure’.

Getting the James Webb telescope into space cost $8 billion. Here we are having spent considerably more than thirty times this and we haven’t even got lift off. I remember when, at the G8 Summit in London in 2013 pharma-funded scientists said ‘within ten years we’ll have a cure. This month, listening to the BBC Radio 4’s ‘Inside Health’ programme on Alzheimer’s, they said exactly the same thing – that magical ten years from now. How can you claim you’ll have a cure when you don’t even know the cause? I predict we’ll be in the same place in ten years if the Alzheimer’s industry don’t quit on amyloid and p-tau.

But it gets worse than this. Despite nothing but evidence to the contrary, based on the completely false notion that ‘Alzheimer’s IS amyloid’ we are being told an amyloid blood test is around the corner. In other words, if you have amyloid blood test but feel completely normal, you’ll likely be told you have ‘pre-clinical Alzheimer’s’ just waiting to happen despite a third of those with amyloid plaques having no problem at all! That’s a conflation upon a conflation.

All this is laid out beautifully in a book by Karl Herrup – Professor of Neurobiology and Investigator at the Alzheimer’s Disease Research Centre at the University of Pittsburg, called How NOT to study a disease – The Story of Alzheimer’s. If you don’t believe what I’m saying, or rightly question it, please read this book. You can find it in our online Bookstore here.

But, so desperate is the medical-pharmaceutical industry to find a treatment and make money that it just can’t give up. It reminds me of the story of Mullah Nasrudin, who is looking at the illuminated ground under a lamp-post. A passer by says ‘what are you looking for?’ The Mullah says ‘I dropped a coin.’ The person says ‘did you drop it around here?’ The Mullah said ‘no, but it’s the only place I can see’.

Curing amyloid won’t cure the disease

But let’s be clear. This doesn’t mean that having lots of amyloid in your brain doesn’t increase the PROBABILITY of getting Alzheimer’s in the future in much the way that being older also increases the probability of getting Alzheimer’s. But it doesn’t cause it. So ‘curing’ amyloid won’t cure the disease. If you ‘exist for a cure’, as one charity claims, you have a start with a clue as to what’s causing it. Obviously not amyloid.

The same thing is happening with another ‘marker’ in the brain called p-tau, which is associated with having more tangled nerves. Tau is a normal protein that becomes an abnormal, toxic protein called p-tau. The ‘p’ stands for phosphorus or ‘phosphorylated’ because there’s an enzyme that adds on the ‘p’ and another that takes it away. Much like amyloid, having more p-tau increases the PROBABILITY of Alzheimer’s but doesn’t cause it. Many people have raised levels of p-tau (we all have some) with no problems at all.

But, by using the same sleight of hand, £10 million has been put up by the Bill Gates Foundation and people funding Alzheimer’s Research UK, to find the blood test for p-tau (I think they’ve already decided on one called p-tau 217) despite no evidence that p-tau CAUSES Alzheimer’s. No doubt, those with raised p-tau 217 will be told they have ‘pre-clinical dementia’ despite no evidence that they do. Of course, if they had a p-tau lowering drug that actually worked as in reducing dementia risk, that might be excusable but they don’t. However, this sleight of hand may be used to sell drugs that don’t work much like ‘cholesterol’ has been used to sell statins.

My cholesterol is slightly high – I have no disease, no risk factors for heart disease, and there is no evidence that lowering my cholesterol will lower my future risk, but still my doctor wants to prescribe me statins. In any case – two thirds of heart attacks in older people are predicted by high homocysteine – not cholesterol.

The only thing I know that does lower p-tau is lowering homocysteine with B vitamins. Homocysteine, a toxic amino acid also found in those with Alzheimer’s and dementia, promote the enzyme that makes p-tau and blocks the enzyme that clears it from your brain as the diagram below shows.

However, talking of homocysteine, it, unlike amyloid and p-tau, is actually causal. That is, lowering homocysteine with B vitamins, stops the accelerated brain shrinkage, stops the cognitive decline and memory loss. That is consistent with a disease-modifying treatment and possibly the only thing for which the evidence could be said to be causal at this point in time.

That doesn’t mean there won’t be other causes. There are some fruitful avenues that have been explored and show real promise. But they have all largely been ignored because of the unhealthy obsession by pharma, the Alzheimer’s societies and government funding bodies on amyloid and tau. These include oxidation – and the role of antioxidants; inflammation; insulin resistance and glucose control; mitochondrial dysfunction – those are the so-called ‘energy’ factories inside every brain cell. Diabetes and dementia are strongly linked, the first often predicting the second. In truth, both homocysteine, which is a measure of a vital process called methylation, oxidation, insulin resistance and inflammation all affect the mitochondria. One clue for inflammation being involved relates to the finding that those with rheumatoid arthritis using heavy duty anti-inflammatory drugs having less risk for Alzheimer’s. In our model of dementia at Food for the Brain glycation, oxidation, methylation and also the vital role of brain fats which actually build the brain are central. I call them the ‘four horsemen of the mental health apocalypse’. The discovery that the homocysteine lowering B vitamins and omega-3 are co-dependent and, together, dramatically slow brain shrinkage and improve cognitive function light years ahead of ANY amyloid or p-tau treatment to date, is of major importance. Yet, this has been largely ignored by the blinkered Alzheimer’s establishment.

So, next time you are asked to donate to Alzheimer’s charities ask them if any of the money is being spent on amyloid or p-tau. If so, I’d suggest politely declining. If instead they are funding research into oxidation, inflammation, homocysteine, insulin or mitochondrial function, then that’s a much better sign your money might not go down a black hole.

Is Alzheimer’s prevention the cure?

But even just focussing on one of these avenues may be misguided. It is based on the current paradigm of medical research – find the thing that is causing the disease then ‘cure’ that. This assumes there is one cause and therefore one treatment. Of course, this is what you need for a drug to make money.

Let’s take homocysteine as an example. Not everyone who develops dementia or Alzheimer’s has high homocysteine. Those who do will reliably develop dementia and lowering it reliably reduces their cognitive decline. So, high homocysteine is a CAUSE, but not the only cause. Insulin resistance leads to diabetes and increases the risk for dementia. So, insulin resistance driven by too much sugar and refined carbohydrates, is probably a cause, but not the only one. There isn’t enough evidence yet to declare ‘cause’ but the evidence that exists points that way.

There is a different way of thinking and researching called system-based science. Much like the straw that breaks the camel’s back this approach presumes there are a number of conditions, not just one, that result in a disease such as Alzheimer’s or dementia. After all, a stroke or head injury can be a cause of cognitive decline even if you don’t have high homocysteine or blood sugar problems. (It could be that a potential causal mechanism that ties these together is cerebrovascular dysfunction – disturbed blood supply to the brain. High homocysteine, by the way, increases risk of this by 17-fold).

In my book Upgrade Your Brain, which gives all the reference studies for statements made in this article, I argue that every known risk factor or biomarker for cognitive decline, dementia or Alzheimer’s affects either the structure, the function or the utilisation of the neuronal network and that it is combinations of these that crank up risk and ultimately brain pathology. We will publish a paper on this soon in a scientific journal.

It’s like saying five critical things have to work for your car to move forward and not crash. Tyre pressure good, brakes working, enough gas, oil and water for the radiator to cool the engine. If any one of these is completely broken the car stops or crashes. If two are not working well, such as low oil and low water, the car grinds to a halt. If a car approaches too close (like a potential head injury) and one tyre is quite flat and the brakes aren’t working well, you crash.

We tend to think in this way in nutrition and lifestyle medicine. It’s the combo of insults – high sugar, high fried foods, lack of veg, too much alcohol, smoking, that breaks the camel’s back. That heart attack is the ‘perfect storm’ of several underlying factors.

The unpopular approach… that works

This systems-based approach isn’t popular in science and very few funders ever put up money to fund this kind of research. Usually, a funder wants to fund one stream of research, possibly a clinical trial of one approach, in the belief that that one factor is the final straw that breaks the camel’s back and a great discovery will be made. The reality is that it is usually combinations of factors that drive risk with the manifestation of the disease itself being the ‘broken back’. Pollution, for example, is a risk factor for dementia…but not in those with good vitamin B6, folate or B12 status, which are the three B vitamins needed for methylation, indicated by lower homocysteine. Methylation is a major mechanism the body uses to detoxify pollutants and toxins.

This is where Food for the Brain’s approach is unique.

By collecting data from people like you who have both taken the Cognitive Function Test and completed the COGNITION questionnaire, and keep doing so, we can look at what drives cognitive function up and down. In other words what breaks the camel’s back or makes it strong. This kind of complex systems-based science has become possible both due to big data gathering such as we are doing, advances in complex statistics, computer power and programming AI algorithms. Our Head of Science, Associate Professor Tommy Wood, is a bit of an expert in this kind of approach to neuroscience.

It is, I believe, the future and why we will probably find no single primary cause for Alzheimer’s, and certainly not amyloid or p-tau, but combinations of diet and lifestyle and other factors that create the tipping point that leads to dementia. Then, we will have the means to prevent this tipping point from ever being reached. In other words, we may discover that prevention is the cure. We hope that you’ll be part of this discovery. By becoming a FRIEND or making a DONATION you help us research what really causes, and prevents Alzheimer’s.

Similarly, if you’re inspired by our mission and would like to support groundbreaking research into the prevention and early detection of cognitive decline, consider investing in the global COGNITION Biobank project. Your contribution will help drive transformative research and create lasting change. To learn more, email us at donations@foodforthebrain.org


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