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How might diabetes lead to Alzheimer’s?

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How might diabetes lead to Alzheimer’s?

New research conducted in mice has provided insights into what’s going on at the molecular level that could cause people with diabetes to develop Alzheimer’s disease.

Diabetes and Alzheimer’s are two of the fastest-growing health concerns worldwide. Diabetes alters the body’s ability to turn food into energy and affects an estimated 1 in 10 US adults. Alzheimer’s, a form of dementia that causes progressive decline in memory and thinking skills, is among the top 10 leading causes of death in the United States.

Diet is known to influence the development of diabetes as well as the severity of its health impacts. To find out how diet could influence the development of Alzheimer’s in people with diabetes, the researchers traced how a particular protein in the gut influences the brain.

In this study, the team found that a high-fat diet suppresses the expression of a protein called Jak3, and that mice without this protein experienced a cascade of inflammation starting with the intestine, moving through the liver and on to the brain.

Ultimately, the mice showed signs of Alzheimer’s-like symptoms in the brain, including an overexpressed mouse beta-amyloid and hyperphosphorylated tau, as well as evidence of cognitive impairment.

The study adds to a growing body of research on the links between Type 2 diabetes and Alzheimer’s disease, which some scientists have called “Type 3 diabetes.” The findings suggest that it should be possible to reduce the risk of Alzheimer’s by keeping diabetes well controlled or avoiding it in the first place, according to researchers.

Narendra Kumar, an associate professor at Texas A&M University in College Station, who led the study, commented: “We think that diabetes and Alzheimer’s disease are strongly linked, and by taking preventative or amelioration measures for diabetes, we can prevent or at least significantly slow down the progression of the symptoms of dementia in Alzheimer’s disease.”

Kumar will present the new research at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, which is being held March 23–26 in San Antonio.

“Liver being the metabolizer for everything we eat, we think that the path from gut to the brain goes through liver,” Kumar said.

His lab has been studying functions of Jak3 for a long time, he added, and they now know that the impact of food on the changes in the expression of Jak3 leads to leaky gut. This in turn results in low-grade chronic inflammation, diabetes, decreased ability of the brain to clear its toxic substances and dementia-like symptoms seen in Alzheimer’s disease.

The good news, according to Kumar, is that it may be possible to stop this inflammatory pathway by eating a healthy diet and getting blood sugar under control as early as possible. In particular, people with prediabetes — which includes an estimated 98 million U.S. adults — could benefit from adopting lifestyle changes to reverse prediabetes, prevent the progression to Type 2 diabetes and potentially reduce the risk of Alzheimer’s.

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Analysis: Why Alzheimer’s prevention is easier, better, safer and cheaper than current approach

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Alzheimer’s experts behind the new Alzheimer’s Prevention Day on May 15 share provide an update on the current picture for Alzheimer’s treatment. 

Everybody wants a cure for Alzheimer’s. The medical industry has spent around $100 billion searching for one and, so far, come up relatively empty-handed with over thirty failed drug trials.

Yet a simple to administer, cheap test could predict Alzheimer’s and allow preventative measures – saving the NHS over £60million a year.

To date, the focus has been on drugs that lower two of the chemical compounds associated with Alzheimer’s and dementia in general – amyloid and p-tau, a pair of messed up proteins that can lead to plaques in the brain and tangled nerves. There is a third compound – an amino acid called homocysteine, that becomes toxic if you have too much, that the drug industry and the Alzheimer’s charities don’t talk about, for reasons that will become clear.

Predicting Alzheimer’s

The actual clinical measures that are used to diagnose Alzheimer’s are a decline in cognitive function and shrinkage of the central area of the brain called the medial temporal lobe. Both changes in cognitive function and brain shrinkage can be picked up thirty years before a diagnosis of Alzheimer’s is made.

Current study

So now a £10 million study is underway to see if a blood test for p-tau, or amyloid, will ‘predict’ if you are more likely to develop the disease and there are plans for a major program to identify those at risk so they can be treated as early as possible.  This sounds sensible but there are serious drawbacks. To begin with not everyone with raised p-tau or amyloid go on to develop Alzheimer’s.

Drawbacks and side-effects

This means, as a recent article in the New York Times entitled, ‘Apparently healthy but diagnosed with Alzheimer’s,’ pointed out, people without a diagnosis or no brain scan showing shrinkage, could well be offered new drug treatments that are, so far, only marginally better than placebos but have awful adverse effects.

These include brain bleeding or swelling which has occurred in more than one in four participants in the last two drug trials and resulted in seven deaths. Medical agencies in the US, EU and UK are reluctant to licence their use but are under a lot of pressure to do so.

So thousands of desperate people with early stage Alzheimer’s or cognitive decline, hoping for a cure, are queuing up to join these drug trials because they perceive these drugs, that so far come with little or no benefit plus highly unpalatable side effects, are a better alternative than doing nothing.

The research

But are there really no alternatives? Well, none that patients are routinely told about. They involve changes in diet and lifestyle, that are very likely to improve your overall health, including that of your brain, and very unlikely to cause damaging side effects.

Almost all money for research, pledged by governments and raised by Alzheimer’s charities, is going in the direction of drug treatments. Alzheimer’s Research UK’s (ARUK) website says, “we exist for a cure”. Yet, most of the money is going toward amyloid and p-tau related research, neither of which has been established as causal. In other words, high levels may just be a consequence of the disease process.

Homocysteine

The same is not true for raised blood levels of homocysteine. If levels rise in the brain, it shrinks faster and cognitive abilities decline. If it goes down, they improve, and brain shrinkage slows. This means that it is causing the damage and so would logically be a target for treatment. The only way to do it, however, is with high dose B vitamins (B6, B12 and folate). Several gold standard, placebo-controlled trials have found this to be very safe and effective. But this approach is not patentable and so yields nothing like a drug profit.

But the benefits of treating homocysteine don’t stop there. It is a much better biomarker of risk for Alzheimer’s than plaque and p-tau both because it is more easily measured and more safely lowered. And when it is lowered, unlike those two, it actually improves cognitive function and slows brain shrinkage by as much as two thirds. It also helps to stop p-tau formation.

Routine checks save £60million a year

Routinely checking homocysteine levels could prevent thousands of cases. Just doing this “could save costs to the UK economy of approximately £60 million per year,” says Dr Apostolos Tsiachristas, Associate Professor in Health Economics at the University of Oxford. His research also estimated it would promote healthy longevity, adding 14 years to life expectancy.

About half of people over 65 have a homocysteine level above 11mcmol/l, which is where it starts to become damaging.

Supporting studies

In one study a third of those treated ended the study with no clinical dementia rating, meaning they could no longer be diagnosed with cognitive impairment. Those with sufficient omega-3 DHA, which is the most important structural fat in the brain, had 73% less brain shrinkage compared to placebo when given the B vitamin treatment. In contrast, in the last anti-amyloid treatment trial, brain shrinkage accelerated by about a fifth in those getting the drug, compared to placebo and not one person achieved a clinical dementia rating of zero.

It should be clear by now, after decades of scientific research that amyloid plaque is not a cause of Alzheimer’s, but a consequence. The same is likely to be true for p-tau tangles.

As an analogy consider your teeth. Is plaque the cause of tooth decay?  Sure, flossing your teeth and getting the plaque scraped off by the dental hygienist helps, but what causes the plaque? The answer is a bad diet – in this case, one high in sugar and low in fibre. Despite fifty years of research there is no ‘cure’ for tooth decay, but it can be prevented. The same concept applies to Alzheimer’s, which is as preventable as tooth decay with the right diet and nutrition and lifestyle – which also happens to include less sugar and more fibre.

Alzheimer’s Prevention

How preventable is Alzheimer’s? It accounts for two thirds of dementia cases. The most conservative figure is 40%. More optimistic estimates say around 80%. Since only one in a hundred cases is caused by genes Alzheimer’s may be entirely preventable in those 99% who do not have the rare causative genes and act early enough to optimise all diet and lifestyle factors. It is not an inevitable consequence of the ageing process as evidenced by the fact that the majority of people don’t get it.

Why the difference in figures?

It’s all to do with what is or isn’t included in prevention studies. The most widely used review for dementia prevention in the UK is the 2020 report of the Lancet Commission, authored by Professor Gill Livingston. Both this and the first edition in 2017 failed to even mention homocysteine, despite being repeatedly sent all the evidence of the undeniable beneficial effects of homocysteine-lowering B vitamins by the Oxford Project to Investigate Memory and Ageing (OPTIMA) at the University, headed by former Deputy Head of Medical Science, Professor David Smith.

This is a major and damaging error and has led to the widespread belief that B vitamin supplements are not part of the usual list of preventive actions. But it should be corrected, especially considering that a US National Institutes of Health study attributes 22% of the risk of Alzheimer’s to raised homocysteine. Also, the best study of all, looking at 396 studies in total, published in 2020, concluded: ‘Homocysteine-lowering treatment seems the most promising intervention for Alzheimer’s disease prevention.’

Other prevention studies you may have read are possibly based on data from the UK Biobank. This major research data bank also ignores homocysteine, not for any malevolent reason but simply because it wasn’t measured when it was enrolling people. So, one of the single biggest risk factors and arguably the simplest to change, is repeatedly ignored.

Given that a conservative half of Alzheimer’s cases could be prevented, shouldn’t half the available research money be spent on prevention? This certainly doesn’t happen at the moment. Of the three leading charities, two spend nothing on prevention. ARUK claim to spend 5% but none of this goes towards B vitamins or other brain-friendly nutrients such as omega-3 or vitamin D. They too ignore homocysteine, and the beneficial effects of lowering in with B vitamins, as first shown in a 2010 Oxford University study they actually helped fund!

Prevention studies are almost always going to under-estimate (never over-estimate) the power of prevention due to excluding risk factors, but also because they largely ignore the ‘1+1=3’ compounding impact of interactive risk factors. B vitamins, for example, don’t work without sufficient omega-3 and omega-3 oils don’t work in people with raised homocysteine, because of a lack of B vitamins. This has been shown in four trials – in the UK, Holland, Sweden and China. The combination of B vitamins given to people sufficient in omega-3 DHA improved the reduction in brain shrinkage from 53% to 73%. Pollution exposure is a risk factor but, in those with lower homocysteine this effect is much reduced. Poor sleep is a risk factor, but less so in those who exercise.

For the past five years leading UK researchers led by neurologist Professor Peter Garrard, who is the Director of the dementia research group in the St George’s, University of London Neuroscience Research Section, have tried to get funding to test the most promising combination – B vitamins and omega-3 – to no avail. Such a trial is badly needed and would cost of a fraction of that being spent on amyloid or p-tau.

So, what if a person does everything right – enough B vitamins to keep homocysteine low, sufficient omega-3, low sugar, high fibre diet, enough vitamin D (Alzheimer’s is four times less likely in those with sufficient vitamin D), and an active physical, intellectual and social lifestyle, plus good sleep and not too much stress?

The only ongoing study and database, the COGNITION Biobank, that assesses all these risk factors as well as including blood tests of four critical biomarkers, homocysteine, omega-3 index, vitamin D and HBA1c, which measures glucose control, is being run by the charity foodforthebrain.org. It describes itself as ‘citizen science’ because anyone can get involved doing a free online Cognitive Function Test, filling in a questionnaire about their diet, lifestyle and medical history, and sending in a blood sample from a home test kit.

So far, over 400,000 people have been tested. But, unlike the £10 million trial, funded by the People’s Lottery, the Gates Foundation, ARUK and the Alzheimer’s Society, it gets no funding. It is literally funded by the citizen scientists who chip in £50 a year and pay for their own tests. Their message is simple: prevention is better than cure – don’t jump.

To test yourself visit foodforthebrain.org. To find out more about prevention visit www.alzheimersprevention.info

References:

These are key papers regarding stated facts in this article.

New York Times article: https://www.nytimes.com/2024/03/04/health/alzheimers-amyloid-diagnosis.html

Homocysteine and p-tau: https://foodforthebrain.org/the-p-tau-delusion/

Donanemab review in the British medical Journal: BMJ 2023;382:p1852

http://dx.doi.org/10.1136/bmj.p1852;

Telegraph reports 7 deaths and brain shrinkage: https://www.telegraph.co.uk/news/2024/02/19/alzheimers-drugs-shrink-brain-scientists-warn/

Health economics of B vitamins: Tsiachristas A, Smith AD. B-vitamins are potentially a cost-effective population health strategy to tackle dementia: Too good to be true? Alzheimers Dement (N Y). 2016 Aug 11;2(3):156-161. doi: 10.1016/j.trci.2016.07.002. PMID: 29067302; PMCID: PMC5651357.

Omega-3 and B vitamin interactions and studies: Smith AD, Jernerén F, Refsum H. ω-3 fatty acids and their interactions. Am J Clin Nutr. 2021 Apr 6;113(4):775-778. doi: 10.1093/ajcn/nqab013. PMID: 33711096.

Less brain shrinkage and cognitive decline with B vitamins and sufficient omega-3: Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD. Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 2015 Jul;102(1):215-21. doi: 10.3945/ajcn.114.103283. Epub 2015 Apr 15. PMID: 25877495; see also  Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. J Alzheimers Dis. 2016;50(2):547-57. doi: 10.3233/JAD-150777. PMID: 26757190; PMCID: PMC4927899.

NIH Alzheimer’s prevention review: Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014 Jun 24;14:643. doi: 10.1186/1471-2458-14-643. PMID: 24962204; PMCID: PMC4099157.

Meta-analysis of 396 studies favouring homocysteine-lowering B vitamin treatment: Prof Yu study Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-1209. doi: 10.1136/jnnp-2019-321913. Epub 2020 Jul 20. PMID: 32690803; PMCID: PMC7569385.

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Ageing fight revealed in new ‘muscle map’

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The first comprehensive cell atlas of ageing human muscle reveals the intricate genetic and cellular processes behind muscle deterioration and mechanisms to counteract it.

How muscle changes with ageing, and tries to fight its effects, is now better understood at the cellular and molecular level with the first comprehensive atlas of ageing muscles in humans.

Researchers from the Wellcome Sanger Institute and their collaborators at Sun Yat-sen University, China applied single-cell technologies and advanced imaging to analyse human skeletal muscle samples from 17 individuals across the adult lifespan. By comparing the results, they shed new light on the many complex processes underlying age-related muscle changes.

The atlas uncovers new cell populations that may explain why some muscle fibres age faster than others. It also identifies compensatory mechanisms the muscles employ to combat ageing.

The findings offer avenues for future therapies and interventions to improve muscle health and quality of life as we age.

This study is part of the international Human Cell Atlas initiative to map every cell type in the human body, to transform understanding of health and disease.

As we age, our muscles progressively weaken. This can affect our ability to perform everyday activities like standing up and walking. For some people, muscle loss worsens, leading to falls, immobility, a loss of autonomy and a condition called sarcopenia. The reasons why our muscles weaken over time have remained poorly understood.

In this new study, scientists from the Wellcome Sanger Institute and Sun Yat-sen University, China used both single-cell and single-nucleus sequencing techniques along with advanced imaging to analyse human muscle samples from 17 individuals aged 20 to 75.

The team discovered that genes controlling ribosomes, responsible for producing proteins, were less active in muscle stem cells from aged samples. This impairs the cells’ ability to repair and regenerate muscle fibres as we age. Further, non-muscle cell populations within these skeletal muscle samples produced more of a pro-inflammatory molecule called CCL2, attracting immune cells to the muscle and exacerbating age-related muscle deterioration.

Age-related loss of a specific fast-twitch muscle fibre subtype, key for explosive muscle performance, was also observed. However, they discovered for the first time several compensatory mechanisms from the muscles appearing to make up for the loss. These included a shift in slow-twitch muscle fibres to express genes characteristic of the lost fast-twitch subtype, and increased regeneration of remaining fast-twitch fibre subtypes.

The team also identified specialised nuclei populations within the muscle fibres that help rebuild the connections between nerves and muscles that decline with age. Knockout experiments in lab-grown human muscle cells by the team confirmed the importance of these nuclei in maintaining muscle function.

Veronika Kedlian, first author of the study from the Wellcome Sanger Institute, said: “Our unbiased, multifaceted approach to studying muscle ageing, combining different types of sequencing, imaging and investigation reveals previously unknown cellular mechanisms of ageing and highlights areas for further study.”

Professor Hongbo Zhang, senior author of the study from Sun Yat-sen University, Guangzhou, China, said: “In China, the UK and other countries, we have ageing populations, but our understanding of the ageing process itself is limited. We now have a detailed view into how muscles strive to maintain function for as long as possible, despite the effects of ageing.”

Dr Sarah Teichmann, senior author of the study from the Wellcome Sanger Institute, and co-founder of the Human Cell Atlas, said: “Through the Human Cell Atlas, we are learning about the body in unprecedented detail, from the earliest stages of human development through to old age.With these new insights into healthy skeletal muscle ageing, researchers all over the world can now explore ways to combat inflammation, boost muscle regeneration, preserve nerve connectivity, and more. Discoveries from research like this have huge potential for developing therapeutic strategies that promote healthier ageing for future generations.”

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UK body calls for more ageing research backing

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The British Society for Research on Ageing (BSRA) is calling for more public backing in the UK for research to help people stay healthier for longer, as an alternative to charities that support research on diseases.

The greatest risk factor for disease is ageing, but we have very little charitable support for research into how to slow ageing, the organisation warns.

Many diseases such as cancers and heart disease tragically shorten lives far too early, or like Alzheimer’s and arthritis, destroy quality of life for patients and carers. There is understandably huge public charitable support for more research. However, the greatest risk factor for those diseases, and even infectious diseases like COVID, is ageing.

Yet in comparison there is currently very little support for research to understand how we can slow ageing to prevent disease. This approach may be more productive in the long term to fight disease. Furthermore, keeping people healthier for longer, or avoiding chronic diseases all together, would be the most favourable outcome.

The UK population is ageing fast, putting pressure on the NHS and the economy. Despite this pressing problem all around us, there is no accessible way for people to support research into ageing in the UK. The BSRA aims to change that.

With a very small budget and almost completely run by volunteers, the BSRA has successfully funded several small research projects but progress needs to be accelerated. More funding is needed because it takes years to see the effects of ageing, so studies are long. Also ageing affects individuals in different ways, meaning that large numbers of people must be studied to make firm conclusions.

Therefore, there is an urgency to get studies funded and the BSRA has decided to launch an ambitious fundraising campaign to boost research into ageing. Initially, the Society aims to fund a series of one year research projects at the Masters degree level at universities across the UK and with plans to raise much more in the future to support longer and more ambitious projects that will impact the lives of the general public.

Chair of the BSRA, Prof David Weinkove from Durham University, says “The time is now to really get behind research into the biology of ageing. We have fantastic researchers across the country, but they are held back by a lack of funding. Evidence-based research is needed to understand how we people can stay healthier for longer, and to then we must make that knowledge available to as many people as possible”.

Dr Jed Lye says “This is a great opportunity for the public to help, for corporations to contribute, or philanthropists wanting a large impact with a relatively small donation; every £20,000 we raise can fund an entire year of research into ageing and longevity, and gets a budding scientist their research qualification.”

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