Tau is a structural protein that helps build the skeleton, much like pipes, through which nutrients and nerve signals are delivered to different parts of the brain. Our brains contain a balance of tau protein and phosphorylated-tau, abbreviated to p-tau. An abnormal accumulation of p-tau makes these tubular channels tangled and dysfunctional and triggers brain-cell death.¹

Too much p-tau also messes up the mitochondria, the cells’ energy factories, potentially leading to brain fatigue. The more p-tau accumulates, the greater the risk of cognitive problems and Alzheimer’s dementia. Also, those with memory decline have been shown to have relatively more p-tau to tau protein.

The next target for dementia drugs is reducing p-tau. Consequently, drugs are being developed and tested that block the kinase enzyme and activate the phosphatase enzyme,² which is exactly what the homocysteine-lowering B vitamins do. But so far, there are no human clinical trials reporting significant benefit.

The critical prevention question is what stops too much of the tau protein from turning into the potentially harmful p-tau in the first place and what helps restore p-tau to normal tau protein.

The answer is remarkably simple – a lack of B vitamins raises the blood levels of homocysteine, which activates an enzyme, Cdk5 kinase, which adds the bad ‘p’ to tau and blocks another enzyme, protein phosphatase A2, which removes the dangerous ‘p’.^3,4 High homocysteine levels also damage the tiny blood vessels in the brain, leading to ‘mini strokes’ or transient ischemic attacks (TIAs), which further raise the levels of p-tau. Homocysteine not only raises the levels of the dangerous p-tau,⁵ but can also bind to tau,⁶ further generating the neurofibrillary tangles that then trigger brain-cell death.

So, the simplest way to stop the formation of p-tau, and neurofibrillary tangles, and keep your brain healthy, is to keep your plasma homocysteine level below 10mcmol/l. Half of those above 65 have a homocysteine level higher than this.

By now you’re surely wondering why, if these natural approaches are at least as good, if not better, than drug treatments, and without adverse effects, why this isn’t common knowledge and common practice, especially if the cost is a fraction of the drug treatments. For example, supplementing B vitamins and omega-3 fish oils might cost you £100 a year while anti-amyloid drugs are pitched at around £20,000 a year.

I’m convinced that it is exactly this last point that explains the anomaly. Naturally occurring nutrients cannot be patented; only a man-made invention, such as a drug, can be. Holding a patent means only the company making that product can sell it, and they can determine the price. The price of a drug will include a hefty margin for marketing the drug and creating all the hype to get you, the media and the medical profession to buy into it. Once the patent expires, the price plummets. The price of a leading branded statin dropped by 93 per cent, from close to £30 down to just over £2 a month,⁷ That’s a lot of margin for marketing. By then, the manufacturers are on to the next ‘new’ patented drug. Up to 2022 $45 billion⁸ has been spent so far developing the latest ineffective dementia drugs, but the real cost, including the most recent trials and marketing, could be double this. That’s a lot of money to recoup. The first stage is to develop a test that convinces you and your doctor that you ‘need’ the drug. That’s what these tests in the £10 million trial are all about. If you test high, instead of taking an ineffective drug why not do prevention? That’s what the free Cognitive Function Test at foodforthebrain.org is all about.

Extract, used with permission, from Patrick Holford’s Upgrade Your Brain (Thorsons 2024)

REFERENCES

1. Balasu S et al. Science14 Sep 2023 Vol 381, Issue 6663 pp. 1176-1182 DOI: 10.1126/science.abp9556

2. Xia, Y., Prokop, S. & Giasson, B.I. “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies. Mol Neurodegeneration 16, 37 (2021). https://doi.org/10.1186/s13024-021-00460-5.

3. Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016 Jul 17;36:211-39. doi: 10.1146/annurev-nutr-071715-050947. PMID: 27431367.

4. LiJ-G,ChuJ,BarreroC,MeraliS,Pratico`D.2014.Homocysteine exacerbatesβ-amyloid, tau pathology, and cognitive deficit in a mouse model of Alzheimer’s disease with plaques and tangles. Ann. Neurol. 75:851–63.

5. Shirafuji N et al Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization. Int J Mol Sci. 2018 Mar 17;19(3):891. doi: 10.3390/ijms19030891. PMID: 29562600; PMCID: PMC5877752.

6. Bossenmeyer-Pourié C et al. N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer’s disease and vascular dementia. J Pathol. 2019 Jul;248(3):291-303. doi: 10.1002/path.5254. Epub 2019 Mar 19. PMID: 307349

7. https://www.pulsetoday.co.uk/news/clinical-areas/cardiovascular/price-of-atorvastatin-plummets-93-as-patent-ends/

8. Cummings JL, Goldman DP, Simmons-Stern NR, Ponton E. The costs of developing treatments for Alzheimer’s disease: A retrospective exploration. Alzheimers Dement. 2022 Mar;18(3):469-477. doi: 10.1002/alz.12450. Epub 2021 Sep 28. PMID: 34581499; PMCID: PMC8940715.

What is HbA1c?

HbA1c stands for Hemoglobin A1c, which is a specific type of protein that glucose becomes attached to. Glucose is a simple sugar that is absorbed into the bloodstream when your body breaks down carbohydrate foods. When glucose is absorbed, some of it becomes attached to the hemoglobin A1c protein and, over time, the more glucose that is circulating in the blood stream, the more glucose becomes attached to the hemoglobin A1c protein. HbA1c is expressed as a percentage because it is the percent of hemoglobin A1c protein that has glucose attached, so if your HbA1c is 5.5% (36.6 mmol/mol), that means that 5.5% of the hemoglobin A1c proteins have glucose attached to them.

Where does blood sugar (glucose) come from?

The main source of sugar in your blood comes directly from the foods you eat. Some examples of these types of foods include rice, potatoes, pasta and bread, as well as sugary foods such as cookies, cakes, and pastries. When glucose enters the bloodstream after you eat carbohydrates, it goes through the pancreas. The pancreas secretes insulin when you consume carbohydrates and sends excess glucose to the liver as glycogen. The pancreases also produces glucagon, which actually raises blood sugar when necessary. You need both glycogen and glucagon to keep blood sugar levels balanced.

What happens when blood sugar (glucose) levels are too high?

Glucose is the primary sugar found in your blood. It is also your body’s main source of energy. However, when there is too much in your blood over a period of time it can damage blood vessels, tissues and organs and potentially lead to serious health issues like diabetes, heart disease and cognitive disorders, as well as vision and nerve problems.

Some signs of high blood sugar include frequent urination, increased hunger and thirst, fatigue, blurred vision, tingling or numbness in the hands or feet, and unexplained weight loss. If you are experiencing any of these, you should immediately consult a health care provider.

What happens when blood sugar (glucose) levels are too low?

Low blood sugar, also called hypoglycemia, is an issue faced most often by diabetics who have taken too much insulin, causing their blood sugar level to drop. This typically requires quick treatment with sugary drinks like orange juice or honey or candy. In severe cases, someone will require a shot of glucagon to bring the level back up. Some of the signs of low blood sugar are an irregular or fast heartbeat, fatigue, sweating, irritability, and tingling or numbness on the lips, tongue and cheeks. In severe cases, hypoglycemia can also cause confusion, loss of consciousness, seizures and blurred vision. If you are experiencing any of these symptoms, you should immediately consult a health care provider.

Do I need to fast for a HbA1c test?

You do not need to fast for the HbA1c test. Unlike other glucose tests, your HbA1c number reflects glucose levels over time, not a quick, one-time snapshot of a current glucose level.

Why HbA1c vs. a fasting glucose test?

A fasting glucose test will give you a great snapshot of your current glucose level. However, fasting glucose can also be affected acutely by a lot of different factors that don’t necessarily reflect your overall glucose metabolism. On the other hand, HbA1c offers you a window into your glucose levels over a longer period (~3 months).

Is the HbA1c Test NGSP-Certified?

The HbA1c method (reagents/kit) that we purchase from the manufacturer is NGSP-certified. This means our test’s reference values are compatible with NGSP reference values.

NGSP stands for National Glycohemoglobin Standardization Program (NGSP), which was implemented to enable laboratories to report DCCT/UKPDS-traceable GHb/HbA1c results.

How often should you take an HbA1c test?

HbA1c should be tested every 2-3 months if you are making diet and lifestyle changes.

Can HbA1c be too low?

While it is possible for your HbA1c to be too low, it is very rare. HbA1c under 4.0% (20.2 mmol/mol) is considered extremely low and is associated with a significant increase in all-cause mortality. Although it is not well understood why a low HbA1c is associated with an increase in all-cause mortality, it is likely because individuals with other conditions such as iron-deficiency anemia, liver diseases/disorders, or inflammatory conditions have lower circulating glucose or lower hemoglobin levels that can affect their HbA1c. If your HbA1c is extremely low, you need to speak with a health care provider to discuss your results.

Who should get their HbA1c tested?

Anyone can benefit from better understanding their health, specifically their glucose metabolism.

I thought only diabetics needed to check their HbA1c. Is that true?

While it is important for diabetics to monitor and manage their HbA1c, anyone can benefit from checking their levels. Being proactive can help you identify areas of your health/lifestyle that may need adjusting. Or if you’ve recently made a change, checking to see if that change is having the desired metabolic effect. Elevated blood glucose is very common and can escalate quickly, so monitoring your HbA1c regularly can help you get a head of any problems down the road.

I’m active, at a healthy weight, and exercise regularly. Do I need to check my HbA1c?

Absolutely. There are so many factors that can affect blood glucose, including stress, sleep, and genetics. Checking your HbA1c can help you determine if your lifestyle is, in fact, supporting a healthy blood sugar level. And if not, you can re-check in 2-3 months when you adjust in your diet or activity.

I don’t eat a lot of desserts or sugary foods. Why should I bother checking my blood sugar?

The term “blood sugar” can be confusing as it implies that only sugary, dessert-type foods will increase blood glucose. Any carbohydrate, even healthy ones such as whole grains, beans, vegetables, and fruits can be broken down into glucose as well. Your body also can produce its own glucose in the liver when it is stressed or deprived of glucose in your diet, so checking your HbA1c can give you an idea of how well your body is regulating glucose and if you might need to make any changes.

I’m on a low carb diet. Do I still need to test my HbA1c?

It is a common misconception that people on a low-carb diet will always have low blood sugar. Although you won’t be taking in much glucose, your body can and will produce it on its own in your liver through a process called gluconeogenesis. In fact, depriving your body of exogenous carbohydrates (via food) can result in an increase in cortisol production, which then triggers the process of gluconeogenesis in your liver. Your liver will produce glucose to feed your organs, specifically your brain, because you are not taking in enough carbohydrates via your diet. So, while decreasing carbohydrates can be an effective way to manage high blood sugar, going too low in carbohydrates can lead to the opposite effect. Therefore, measuring your HbA1c while making any dietary changes is still very important.

Research Professor Tommy Wood from the University of Washington, explains

So, what are the top lifestyle choices to keep our brains sharp into old age? As a
neuroscientist, this is a question I often get. Besides the obvious ones – physical activity,
strength, sleep, a healthy diet, not smoking – my top tip is this: If you want to stay mentally
sharp into old age, keep your brain active. In short, “use it or lose it”. But what does “using
it” look like? In this post I’ll cover some of the evidence around cognitive decline, as well as
some practical take-aways for anybody wanting to improve their brain health as they get
older.

Use it or lose it

The brain is an amazing organ, and it’s more resilient and adaptable than we’ve been led to believe. I’m sure you’ve heard that adults have a fixed amount of brain cells. Then, as we get older (or every time we take a sip of wine) we “lose” some of those brain cells as part of an unstoppable decline towards dementia or Alzheimer’s disease.

But that’s not necessarily true. I like to think about the brain like I think about muscles. In order to grow our muscles, we need to provide a stimulus – like lifting weights in the gym – followed by a period of rest. The opposite also happens – if we stop going to the gym or if we stop using a limb after breaking a bone – our muscles get smaller. Most have experienced this personally, and there’s every indication that your cognitive “muscle” behaves in the same way.

How do we know this? One type of evidence is that longer education seems to reduce dementia in later life. [2]* You might think of education as early cognitive muscle building that you then benefit from throughout life. We see similar effects from other forms of early cognitive stimulus – like protection from neurodegenerative disease in people who grew up bilingual.[3]

But we’re not cognitively doomed after adolescence. One of my favourite studies looked at adults studying “The Knowledge” – memorising ~25,000 streets in central London to become a taxi driver. These participants were in their 30s or 40s, yet they saw a significant increase in the size of the hippocampus, the brain region associated with memory.[4]

We also see the opposite effect – less cognitive stimulus increases the risk of cognitive decline and dementia. This is most easily studied by looking at retirement. Multiple studies in populations across the US, China, and Europe, show that the risk of cognitive decline accelerates after retirement.[5-8] Those that retire later are protected against cognitive decline, even after considering factors that might force early retirement such as poor health. Overall, a recent meta-analysis looking at health and lifestyle factors associated with cognitive decline found that cognitive activity was the single most protective factor – halving the risk of Alzheimer’s disease.[2] This really emphasises the lesson: use it or lose it. What counts as ‘protective cognitive demand’? Doing something badly.

The evidence around retirement and cognitive decline suggests that work is where adults tend to get most of their cognitive activity. However, it’s important to unpick what constitutes cognitive activity that is protective. We may feel that our work demands a lot from our brain, but being “busy” does not necessarily benefit the brain. In fact, it’s often the opposite. Being “busy” tends to come with stress, and though stress is very personal, chronic stress is associated with an increased risk of Alzheimer’s disease.[9] What keeps us busy and stressed – sitting in meetings, reading emails, inputting data – may be time consuming, but rarely requires much brain power.

So, what constitutes protective cognitive demand? Failure.

Activities that provide the greatest cognitive stimulus involve learning and skill development. That means we’re initially bad at them and occasionally fail before we get better. This is the real sticking point for improving brain health – as adults we hate the feeling of being bad at something. Failing is, however, when the magic happens. A fascinating study looked at the brains of musicians.[10] While both professional and amateur musicians’ brains looked younger compared to non-musicians of the same age, the benefit was greatest in amateur musicians. The researchers suggested that playing music is more of a cognitive stimulus for amateurs – it’s harder, so they get more benefit. The cocktail of hormones released as we try, fail, repeat, and learn, provides the ideal environment for the brain to grow and adapt.

How to “use it”

So, how should we apply this knowledge? Below are some of the best and easiest ways to build in cognitive stimuli you can benefit from for years to come.

1 | Pick an activity that’s truly challenging
Cognitive demand requires failure, so pick something you’ll be bad at initially. What’s cognitively challenging is personal, but learning a new language is better than sudoku, building model airplanes is probably better than reading the news, and playing chess is definitely better than scrolling through Instagram. As you get better, add challenge to keep stimulating your brain.

2 | Start small and do something you enjoy
Skill development should be a lifelong process, which means it should be a routine. Start small – for instance 2 minutes a day of playing an instrument or learning a new language. Make sure your new skill is something you enjoy – that makes it easier to stick to and keep as a part of your life.

3 | Move – with a skill component
Movement has some of the best evidence on improving brain health. One of the first studies to show that the hippocampus can grow in adults of retirement age (or older) used a walking intervention – just 40 minutes of brisk walking 3x per week.[11] Other studies have showed increased brain connectivity and function in adults doing resistance training 1-2 times per week.[12] Best is movement that includes balance or motor skills: the added challenge of coordination seems to be particularly protective against cognitive decline.[13] Think yoga, dance, or even skateboarding!

4 | Try a new skill that’s social
Social interaction is its own form of cognitive stimulus: social connection is protective of cognitive function, while social isolation has the opposite effect.[14]So what’s better than simply learning a new skill? Doing so with friends. Start a book club to discuss the books you read. Join a knitting circle, language group, or dance class. Volunteer for a local charity. All of these help you learn new skills, with the added benefit of social interaction.

5 | Repeat, repeat, repeat
There are no hard and fast rules about how much or how often to work on a new skill, but once a week is a good start. If it’s a class or a movement practice, maybe 1-3 times per week. If it’s something you can do on your own, you may prefer more frequent, smaller bouts of focused practice. Try using a Pomodoro timer to dig in for 20-30 minutes – a suitable time for most people to keep their undivided attention.
The key is to push right at the boundaries of what you’re capable of – with occasional failure showing that you’re at the right level of difficulty. Keep at it, and you’ll be more likely to be healthy and sharp for decades to come.

Footnote
*It’s worth noting that those who stay in education for longer also tend to be socioeconomically advantaged, but the benefit of longer education seems to hold even accounting for that.

References

Lourida I, Hannon E, Littlejohns TJ, Langa KM, Hyppönen E, Kuźma E, Llewellyn DJ. Association of Lifestyle and Genetic Risk With Incidence of Dementia. Jama. 2019;322(5):430-7. doi: 10.1001/jama.2019.9879.
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;91(11):1201-9. Epub 2020/07/22. doi: 10.1136/jnnp-2019-321913. PubMed PMID: 32690803; PMCID: PMC7569385.
Sala A, Malpetti M, Farsad M, Lubian F, Magnani G, Frasca Polara G, Epiney JB, Abutalebi J, Assal F, Garibotto V, Perani D. Lifelong bilingualism and mechanisms of neuroprotection in Alzheimer dementia. Hum Brain Mapp. 2022;43(2):581-92. Epub 2021/11/04. doi: 10.1002/hbm.25605. PubMed PMID: 34729858; PMCID: PMC8720191.
Woollett K, Maguire EA. Acquiring “the Knowledge” of London’s layout drives structural brain changes. Current biology : CB. 2011;21(24):2109-14. Epub 2011/12/08. doi: 0.1016/j.cub.2011.11.018. PubMed PMID: 22169537.
Hale JM, Bijlsma MJ, Lorenti A. Does postponing retirement affect cognitive function? A counterfactual experiment to disentangle life course risk factors. SSM – Population Health. 2021;15:100855. doi: https://doi.org/10.1016/j.ssmph.2021.100855.
Dufouil C, Pereira E, Chêne G, Glymour MM, Alpérovitch A, Saubusse E, Risse- Fleury M, Heuls B, Salord JC, Brieu MA, Forette F. Older age at retirement is associated with decreased risk of dementia. Eur J Epidemiol. 2014;29(5):353-61. Epub 2014/05/06. doi: 10.1007/s10654-014-9906-3. PubMed PMID: 24791704.
Nikolov P, Adelman AM. Do Pension Benefits Accelerate Cognitive Decline? Evidence from Rural China. Labor: Public Policy & Regulation eJournal. 2019. Sundström A, Rönnlund M, Josefsson M. A nationwide Swedish study of age at retirement and dementia risk. Int J Geriatr Psychiatry. 2020;35(10):1243-9. Epub 2020/06/20. doi: 10.1002/gps.5363. PubMed PMID: 32557831.
Ye Y, Li J, Yuan Z. Effect of antioxidant vitamin supplementation on cardiovascular outcomes: A meta-analysis of randomized controlled trials. PloS One. 2013;8:e56803. doi:10.1371/journal.pone.0056803.
Rogenmoser L, Kernbach J, Schlaug G, Gaser C. Keeping brains young with making music. Brain Struct Funct. 2018;223(1):297-305. Epub 2017/08/18. doi: 10.1007/s00429-017-1491-2. PubMed PMID: 28815301.
Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF. Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences. 2011;108(7):3017. doi: 10.1073/pnas.1015950108.
Herold F, Törpel A, Schega L, Müller NG. Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements – a systematic review. Eur Rev Aging Phys Act. 2019;16:10. Epub 2019/07/25. doi: 10.1186/s11556-019-0217-2. PubMed PMID: 31333805; PMCID: PMC6617693.
Ludyga S, Gerber M, Pühse U, Looser VN, Kamijo K. Systematic review and meta- analysis investigating moderators of long-term effects of exercise on cognition in healthy individuals. Nature Human Behaviour. 2020;4(6):603-12. doi: 10.1038/s41562-020-0851-8.
Penninkilampi R, Casey AN, Singh MF, Brodaty H. The Association between Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2018;66(4):1619-33. Epub 2018/11/20. doi: 10.3233/jad- PubMed PMID: 30452410.