By Sophie Barret – Hifas da Terra & Patrick Holford

Two medicinal mushrooms are particularly relevant when it comes to optimising your brain health, here we discuss Reishi (Ganoderma Lucidum) and Lion’s Mane (Hericium erinaceus); in terms of their potency and use in both Alzheimer’s and Dementia as well as the studies and clinical research into both these significant strains.

Alzheimer’s disease is the most common form of dementia and, according to the WHO, accounts for 60-70% of cases. It is a progressive neurological disorder that involves a steady decline in thinking, behaviour and social skills that affects a person’s ability to live independently. Although age is the main risk factor for dementia, the disease is not an inevitable consequence of ageing. This type of dementia does not exclusively affect older people. Early-onset dementia (onset of symptoms before the age of 65) accounts for up to 9% of cases. Regular physical and mental exercise, avoiding cigarette smoke and alcohol, controlling weight and blood pressure, as well as following a healthy diet and premium quality supplementation can reduce the risk of Alzheimer’s or even slow down the process.

The application of Mycotherapy for Alzheimer’s focuses on the use of pure, standardised, organic extracts of Lion’s Mane (Hericium erinaceus) and Reishi (Ganoderma lucidum), the supplementation of which has been associated in clinical studies with a reduction in the likelihood of mild cognitive impairment and in vivo with anti-dementia activity in cognitive deficits.

The neurodegenerative mushroom: lion’s mane

Lion’s Mane, (Hericium erinaceus) is a medicinal mushroom with diverse pharmacological activities in the prevention of many age-associated neurological dysfunctions, including Alzheimer’s disease and Parkinson’s disease. (5). Supplementation of H. erinaceus has been shown to improve cognitive function and memory in people with mild cognitive impairment (4) and slow cognitive decline and dementia. Its extract is highly recommended in the treatment of neurodegenerative diseases.

The action of Lion’s Mane is based both on its ability to regenerate damaged nerve axons and to enhance myelinization. This is thanks to the rich content of hericenones found in Lion’s mane extract that act as a Nerve Growth Factor (NGF) enhancing agent.

European Biotech, Hifas da Terra, conducted the Neurofood study in people using a unique Lion’s Mane strain. The results showed significant improvements in participants’ attention, memory, concentration, processing speed and visuospatial skills.

The neuroprotective mushroom: reishi

Reishi has demonstrated neuroprotective capacity due to its potent antioxidant properties. Thanks to the antioxidant capacity of G. lucidum’s active biomolecules, especially terpenes such as ganoderic acid, it can improve the reduction of age-related oxidation linked to impaired cognitive function (12,13,14), alleviating neuronal damage and inhibiting apoptosis in Alzheimer’s disease (15).

Several studies and reviews have demonstrated its preventive and therapeutic effect on neuronal damage and cognitive impairment (9).

The antioxidant effect of G. lucidum, thanks to the ability of its active ingredients to scavenge free radicals, may enhance the reduction of age-related oxidation linked to cognitive function decline. (10).

What about ‘magic mushrooms’ & psychedelics ?

One of the hottest areas of brain research is the effects of various hallucinogenic compounds, notably psilocybin – a hallucinogenic substance in certain types of mushrooms, but also LSD and the Amazonian plant potion Ayahuasca, a rich source of DMT, on mental health and brain function. These compounds are tryptamines and share a quality of activating a key receptor site in the brain for serotonin, called 5-HT2 receptors.  As a group, they are all shown to be potential promoters of neuroregeneration and neuroplasticity, helping make neuron connections and perhaps new neurons. They also stimulate brain-derived neurotrophic factor (BDNF), a key brain signaller that stimulates growth. 

With many studies (13) now showing the potential of psychedelics to help those with treatment-resistant depression, drug addiction and also anxiety in terminal patients, much attention is being focussed on what they actually do in the brain. On a psychological level, breakthroughs in debilitating depression and anxiety seem to occur through the experience of patients ‘exorcising the demons’ of early traumas through psychotherapy assisted trips. But there may be more going on at a biological level. Also, studies are underway testing less heroic doses – microdoses – of these agents. It is too early to say whether they could have a helpful role in those with early cognitive decline and brain shrinking but it is certainly plausible and an area of ongoing research. It’s a case of ‘watch this space’.

In summary, the application of Mycotherapy for any type of dementia seeks to provide a neuroprotective effect, improving quality of life. It focuses also on the use of pure, standardised organic extracts of Lion’s Mane (Hericium erinaceus) and Reishi (Ganoderma lucidum), the supplementation of which has been associated in clinical studies with a reduction in the probability of suffering mild cognitive impairment (MCI) and in vivo with anti-dementia activity in cognitive deficits.

Lion’s Mane, (Hericium erinaceus) is a medicinal mushroom with a variety of pharmacological activities in preventing many age-associated neurological dysfunctions, including Alzheimer’s and Parkinson’s (1). As mentioned, supplementation of H. erinaceus (Lion’s Mane) has been shown to improve cognitive function and memory in people with mild cognitive impairment (2) and is therefore highly recommended in the integrative treatment of neurodegenerative diseases.

The action of H. erinaceus is based both on its ability to regenerate myelin and to regenerate new synapses thanks to its content of hericenones and erinacines, which act as Nerve Growth Factor (NGF) enhancing agents, both at the level of expression and secretion. This contribution of Hericium erinaceus has been shown to both prevent (5) and slow cognitive decline and dementia, as well as showing neuroprotective effects.

Several studies and reviews have also demonstrated as mentioned the neuroprotective capacity of Reishi, (Ganoderma lucidum), as well as its preventive and therapeutic effect on neuronal damage and cognitive impairment (9). While other studies have demonstrated its antioxidant effect concluding that, thanks to the ability of its active ingredients to scavenge free radicals, can enhance the reduction of age-related oxidation linked to the (10)

If you are going to consider two medicinal mushrooms for both these conditions these are the two medicinal mushrooms with the most scientific research behind them.

Want to learn more about how medicinal mushrooms can support you brain and mental health? Join us for the Mushrooms & the Mind webinar!

Click here to join the webinar

Thank you for reading!

Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

References

1. Li IC, Chang HH, Lin CH, et al. Prevention of Early Alzheimer’s Disease by Erinacine A-Enriched Hericium erinaceus Mycelia Pilot Double-Blind Placebo-Controlled Study. Front Aging Neurosci. 2020;12:155. Published 2020 Jun 3. doi:10.3389/fnagi.2020.00155.

2. Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T (2009) Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytotherapy Research 23, 367-372.

3. Kim, Y. O., Lee, S. W., & Kim, J. S. (2014). A comprehensive review of the therapeutic effects of Hericium erinaceus in neurodegenerative disease. Journal of Mushroom, 12(2), 77-81.

4. Mori K, Obara Y, Hirota M, Azumi Y, Kinugasa S, Inatomi S, Nakahata N (2008) Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells. Biologicaland Pharmaceutical Bulletin 31, 1727-1732.

5. Li IC, Lee LY, Tzeng TT, et al. Neurohealth Properties of Hericium erinaceus Mycelia Enriched with Erinacines. Behav Neurol. 2018;2018:5802634. Published 2018 May 21. doi:10.1155/2018/5802634.

6. Kawagishi, H., Zhuang, C., & Yunoki, R. (2008). Compounds for dementia from Hericium erinaceum. Drugs of the Future, 33(2), 149.

7. Ma BJ, Shen JW, Yu HY, Ruan Y, Wu TT, Zhao X (2010) Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus. Mycology 1,

8. Moldavan M, Grygansky AP, Kolotushkina OV, Kirchhoff B, Skibo GG, Pedarzani P (2007) Neurotropic and trophic action of Lion’s Mane mushroom Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) extracts on nerve cells in vitro. International Journal of Medicinal Mushrooms 9, 15-28.

9. Yu, N., Huang, Y., Jiang, Y., Zou, L., Liu, X., Liu, S., … & Zhu, Y. (2020). Ganoderma lucidum triterpenoids (GLTs) reduce neuronal apoptosis via inhibition of ROCK signal pathway in APP/PS1 transgenic Alzheimer’s disease mice. Oxidative medicine and cellular longevity,

10. Huang, S., Mao, J., Ding, K., Zhou, Y., Zeng, X., Yang, W., … & Pei, G. (2017). Polysaccharides from Ganoderma lucidum promote cognitive function and neural progenitor proliferation in mouse model of Alzheimer’s disease. Stem cell reports, 8(1), 84-94.

11. Klaus AS, Kozarski MS, Nikšić MP (2011) Antioxidant properties of hot water extracts from carpophore and spores of mushroom Ganoderma lucidum. Proceedings for Natural Science, Matica Srpska Novi Sad 120, 277-286.

12. ozarski MS, Klaus AS, Nikšić MP (2011) Extract from wild strain of mushroom Ganoderma lucidum as natural antioxidant. Proceedings for Natural Science, Matica Srpska Novi Sad 120, 287-295.

13. Saeger HN, Olson DE. Psychedelic-inspired approaches for treating neurodegenerative disorders. J Neurochem. 2022 Jul;162(1):109-127. doi: 10.1111/jnc.15544. Epub 2021 Dec 5. PMID: 34816433; PMCID: PMC9126991.

Everyone knows that vitamin D is vital for healthy bones and a stronger immune system but could low levels also be a major driver of Alzheimer’s and  age-related cognitive decline?

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What new research is saying

New research suggests they could, and that levels of vitamin D commonly found in the UK are accelerating cognitive decline and increasing the risk of a dementia diagnosis (1). Supplementing vitamin D, especially in the winter, may reduce future dementia risk.

And it’s not just the UK. A study in France showed that those with low vitamin D levels, below 50nmol/l, had a nearly three-fold increased risk of Alzheimer’s (2). In the UK, over 60 percent of people aged 11 and over have lower levels than this (3).

Supplements also help ward off dementia, according to a large-scale study earlier this year involving over 12,000 dementia-free 70+ year olds (4). More than a third (37%) took supplements of vitamin D and had a 40% lower incidence of dementia. Professor Zahinoor Ismail, of the University of Calgary and University of Exeter, who led the research, said: “We know that vitamin D has some effects in the brain that could have implications for reducing dementia, however so far, research has yielded conflicting results. Overall, we found evidence to suggest that earlier supplementation might be particularly beneficial, before the onset of cognitive decline.”

Did you know we just launched our at-home vitamin D blood tests and MIND Vitamin D Research Project? Will you join our research project and test and track your own vitamin D with us?

Find out more here.

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If you’re not supplementing vitamin D in the winter they are heading for cognitive decline…

Vitamin D expert and Director of the Sunlight, Nutrition and Health Research Center in San Francisco and a member of our Scientific Advisory Board, Dr William Grant, says we’ve vastly under-estimated the importance of vitamin D on the brain and how much you need.

 “All the evidence for bone and immune health shows that you need a blood level of vitamin D above 75nmol/l to be healthy, and the same is proving true for the brain. This optimal level is impossible to achieve without supplementation in the winter. I recommend every adult and teenager supplement 3,000iu a day from October to March. The government’s recommendation of 400iu (10mcg) is not enough for optimal brain health. Supplementing 800iu (20mcg) a day for 12 months has already been shown to improve cognitive function but you need more than this to achieve anything close to an optimal level.” says Dr Grant. “If you’re not supplementing vitamin D in the winter they are heading for cognitive decline.” Yet only eight percent of UK adults take vitamin D in the winter, says the British Nutrition Foundation (6).

Under the direction of Dr Grant, we have launched a research project to test both vitamin D levels, using a home test kit, and cognitive function, with a free online Cognitive Function Test.

“We have tested over 400,000 people’s cognitive function and now we want to discover their vitamin D levels. This will establish how much vitamin D you really need to stay free from dementia” says Dr Grant.

If you’d like to take part in this research and discover your vitamin D level and cognitive function click here . The free online Cognitive Function test also works out what’s driving future dementia risk and tells you what to do about it

Did you know we just launched our at-home vitamin D blood tests and MIND Vitamin D Research Project? Will you join our research project and test and track your own vitamin D with us?

Find out more here.

Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

References

1 Chai B et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an
updated meta-analysis. BMC Neurol. 2019 Nov 13;19(1):284. doi: 10.1186/s12883-019-
1500-6. PMID: 31722673; PMCID: PMC6854782.

2 Jia J et al. Effects of vitamin D supplementation on cognitive function and blood Aβ-related
biomarkers in older adults with Alzheimer’s disease: a randomised, double-blind, placebo-
controlled trial. J Neurol Neurosurg Psychiatry. 2019 Dec;90(12):1347-1352. doi:
10.1136/jnnp-2018-320199. Epub 2019 Jul 11. PMID: 31296588.

3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353432/pdf/nutrients-12-01868.pdf
4 Ghahremani M et al. Vitamin D supplementation and incident dementia: Effects of sex,
APOE, and baseline cognitive status. Alzheimers Dement (Amst). 2023 Mar 1;15(1):e12404.
doi: 10.1002/dad2.12404. PMID: 36874594; PMCID: PMC9976297.

5 Płudowski P et al Guidelines for Preventing and Treating Vitamin D Deficiency: A 2023
Update in Poland. Nutrients. 2023 Jan 30;15(3):695. doi: 10.3390/nu15030695. PMID:
36771403; PMCID: PMC9920487.

6 Ames BN, Grant WB, Willett WC. Does the High Prevalence of Vitamin D Deficiency in
African Americans Contribute to Health Disparities? Nutrients. 2021 Feb 3;13(2):499. doi:
10.3390/nu13020499. PMID: 33546262; PMCID: PMC7913332.

7 Engelsen O. The relationship between ultraviolet radiation exposure and vitamin D status.
Nutrients. 2010 May;2(5):482-95. doi: 10.3390/nu2050482. Epub 2010 May 4. PMID:
22254036; PMCID: PMC3257661.

8 Ekwaru JP et al The importance of body weight for the dose response relationship of oral
vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers. PLoS
One. 2014 Nov 5;9(11):e111265. doi: 10.1371/journal.pone.0111265. PMID: 25372709;
PMCID: PMC4220998.
9 Feart C et al.. Associations of lower vitamin D concentrations with cognitive decline and
long-term risk of dementia and Alzheimer’s disease in older adults. Alzheimers Dement.
2017 Nov;13(11):1207-1216. doi: 10.1016/j.jalz.2017.03.003. Epub 2017 May 16. PMID:
28522216.

10 https://apigateway.agilitypr.com/distributions/history/4db5dd81-e4c6-4503-b961-
ca44baed4423

By Patrick Holford

Did you know the length of your shadow can tell you if you’re able to generate vitamin D from sunlight?

If your shadow is longer than your body – you can’t produce vitamin D from sunlight. If you are in winter and live in a country of higher latitude (like the UK), this is happening now!

Vitamin D is an all-rounder as far as your brain and mental health is concerned.

It helps neurotransmission and exerts anti-inflammatory and neuroprotective activities within the brain by reducing both inflammation and oxidative stress (1).  

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We are all deficient in winter

Generally speaking, the lower your vitamin D, the worse your mood which makes vitamin D especially important to supplement from October to March if you live in the UK or a similar latitude, when the angle of the sun is too low and you’re also less likely to get outdoors exposing your skin to sunlight. It’s best to assume that we are all deficient in winter, unless you travel to the sun, and therefore need to supplement at least 25mcg (1000iu) although two or three times may be optimal and necessary to correct deficiency.

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Vitamin D and depression

The lower your vitamin D level, the more depressed you are likely to feel. If your mood takes a dip in winter months this is a key sign that you might need more. That’s what researchers at the University of Tromso in Norway found on testing 441 volunteers who were given a test for depression and also a test for blood levels of vitamin D. The volunteers were then given Vitamin D supplements or placebo. Tested one year on, those given vitamin D, but not those given the placebos, had substantially lower depression ratings (2).

However, you don’t have to wait for a year to get a lift in your mood. An eight-week study in Australia found that some of those given vitamin D supplements had an improvement in mood in only five days (3). Another study, in Iran, gave a single vitamin D injection and reported improvement in depression when measured 3 months on (4).

Since vitamin D stores, there is no need to supplement daily. You can take a weekly dose. In the Norwegian study above they gave 20,000iu or 40,000iu weekly. Both worked and there wasn’t a big difference in the effects on mood. So, you can assume that 20,000iu weekly, or 3,000iu daily would likely be sufficient.

It’s what is in your blood that matters

However, the yardstick for what you need is really whatever gets your blood level into the optimal range.

In the study above, those given 20,000iu a week averaged a blood level of 88 nmol/l, while those given 40,000iu averaged 111nmol/l. It is now well recognised that levels above 75nmol/l (30 ng/ml) correlate with good health for many health measures, while levels above 100nmol/l (40ng/ml) might be even better in some respects. My recommendation is to test yourself and consider anything below 50 to be deficient, and above 75 to be sufficient with an optimal level being closer to 100nmol/l (40ng/ml). If you then supplement 3,000iu daily, or seven times this weekly, especially from October to March, retest yourself against these yardsticks.

It’s not JUST about vitamin D

But it isn’t just vitamin D we need – it’s sunlight.

During the summer months, if you are spending half an hour outdoors, with short sleeves, shorts or even more skin exposure, in the sunlight, even a multivitamin that provides you 800iu (a quarter of what you need in the darker months) might be sufficient.

Sunlight promotes serotonin, the happy neurotransmitter.

Having good vitamin D levels is a vital part of your brain upgrade since it helps optimise your brain’s serotonin levels. That’s because a vital enzyme called TPH, which converts the amino acid tryptophan into serotonin, is enhanced in the brain by vitamin D, and selectively shut down in the gut. So, with sufficient vitamin D you get higher brain levels of serotonin, promoting good mood, and lower serotonin levels in the gut (5), protecting against gut inflammation. 

The other way to boost your light exposure is with light therapy. Canadian researchers compared the effects of an anti-depressant (fluoxetine), placebo or 30 minutes daily of light therapy as soon as possible on waking for people with major depression. Light therapy was both superior to placebo and anti-depressants, which were also no better than placebo. I have a full spectrum light in my study, which I put on in the winter, when I’m writing in the early morning, before the sun comes up.

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Vitamin D and addiction

Interestingly, vitamin D deficiency is also associated with greater opioid addiction (7), suggesting the need to up vitamin D intake to reduce cravings. There’s also something else interesting about vitamin D, sun exposure and addiction. People can become addicted to sunbeds. In relation to opioids, the lower one’s vitamin D levels, the more addictive they become. Sun exposure, which promotes higher vitamin D levels, reduces opioid addiction.

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What to eat?

The best food sources of vitamin D are oily fish and eggs. A serving of salmon or mackerel is likely to give you 400iu of vitamin D. Two eggs will provide about 130iu. In some countries, not the UK, milk is fortified with vitamin D but otherwise, it is not a great source. Some mushrooms are purposely fortified with vitamin D by exposing them to UV light.

In summary, the way up from down is to eat a low GL diet, with plenty of oily fish and eggs, avoid sugar, cut back on stimulants and alcohol, and make sure your daily supplements include omega-3, B vitamins, with extra B12 if your homocysteine level is high, vitamin D, zinc, magnesium, chromium, plus the amino acids 5-HTP with is the precursor of serotonin.

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Vitamin D protects your brain and memory.

Vitamin D deficiency increases the risk of Alzheimer’s (9). In a study in France involving 912 elderly patients followed for 12 years, a total of 177 dementia cases occurred. Those with low vitamin D levels had a nearly three-fold increased risk of Alzheimer’s (10). Supplementing 800iu (20mcg) a day for 12 months has also been shown to improve cognitive function (11). 

Supplements may also help ward off dementia, according to a recent, large-scale study involving over twelve thousand dementia-free 70+ year-olds in the US (12). More than a third (37%) took supplements of vitamin D. Those who did had a 40% lower incidence of dementia. Professor Zahinoor Ismail, of the University of Calgary and University of Exeter, who led the research, said: “We know that vitamin D has some effects in the brain that could have implications for reducing dementia, however so far, research has yielded conflicting results. Overall, we found evidence to suggest that earlier supplementation might be particularly beneficial, before the onset of cognitive decline.”

—

Vitamin D helps recovery from strokes and brain injury

Having a higher vitamin D level or supplementing vitamin D at levels above 2,000iu a day also helps people recover from strokes (13) and other forms of brain injury.

I recommend 3,000iu a day or 21,000iu a week in winter but most importantly, monitoring your vitamin D level to keep it above 75nmol/l (30 ng/ml). A level of 100nmol/l may be optimal. That is why testing is so vital as winter approaches. Test again 3 months later so you know if you’re taking enough or too much and that will give you a good gauge as spring approaches when you can probably lower your intake to 600 to 1,000iu depending on sun exposure and diet to top up to over 1,000iu.

Vitamin D is vital in pregnancy and for children

A breastfeeding mother must, at least, supplement omega-3 fish oils and ensure enough B vitamins for homocysteine to be below 7 mcmol/L, but many other nutrients are also necessary. Low vitamin D status in both the mother and newborn baby increases the likelihood of developing autistic spectrum disorder by 54% (14).

Without sufficient nutrients not only do brain cells not make the connections but the production and flow of neurotransmitters doesn’t happen optimally. Bruce Ames, Emeritus professor of Biochemistry and Molecular Biology at the University of California, thinks that “serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).” He says that ”insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression in children”. (15) 

A study in Northern Ireland found that half of schoolchildren were deficient in vitamin D, with a level below 50nmol/l (I recommend above 75 nmol/l). Another finds that low vitamin D levels in childhood are related to behaviour problems in adolescence (16). Is it any wonder so many children are neurodivergent?

A placebo-controlled trial giving ADHD children magnesium together with vitamin D for eight weeks showed a major reduction in emotional, conduct and peer problems and improved socialisation compared with children treated with the placebo (17).

—

The bottom line – we all need to supplement vitamin D

The bottom line is everyone, from children to older people, and especially anyone considering pregnancy, suffering with low mood or memory problems, must test their vitamin D, ideally, at the start of winter to guide them as to what to supplement, during winter perhaps at 3 months, and 6 months later, to learn what amount of vitamin D supplementation they need in summer and winter.

In summary, you want to get your blood level above 75nmol/l (30 ng/ml) which usually means supplementing 3,000iu from October to March for those in the Northern Hemisphere. The optimal level is, however,  likely to be above 100nmol/l (40mg/ml).  Your need for vitamin D is likely to be greater if you are overweight and have darker skin and live further North.

When spring returns, and throughout summer, 1,000iu a day may be enough depending on your sun exposure.

Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

References

¹ Jayedi A, Rashidy-Pour A, Shab-Bidar S. Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response †. Nutr Neurosci. 2019 Nov;22(11):750-759. doi: 10.1080/1028415X.2018.1436639. Epub 2018 Feb 15. PMID: 29447107

² Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008 Dec;264(6):599-609. doi: 10.1111/j.1365-2796.2008.02008.x. Epub 2008 Sep 10. PMID: 18793245.

³ Khoraminya N, Tehrani-Doost M, Jazayeri S, Hosseini A, Djazayery A. Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust N Z J Psychiatry. 2013 Mar;47(3):271-5. doi: 10.1177/0004867412465022. Epub 2012 Oct 23. PMID: 23093054. Xxxx check the some in 5 days

⁴ Mozaffari-Khosravi H, Nabizade L, Yassini-Ardakani SM, Hadinedoushan H, Barzegar K. The effect of 2 different single injections of high dose of vitamin D on improving the depression in depressed patients with vitamin D deficiency: a randomized clinical trial. J Clin Psychopharmacol. 2013 Jun;33(3):378-85. doi: 10.1097/JCP.0b013e31828f619a. PMID: 23609390.

⁵ Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 2014 Jun;28(6):2398-413. doi: 10.1096/fj.13-246546. Epub 2014 Feb 20. PMID: 24558199.

⁶ Lam RW, Levitt AJ, Levitan RD, Enns MW, Morehouse R, Michalak EE, Tam EM. The Can-SAD study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry. 2006 May;163(5):805-12. doi: 10.1176/ajp.2006.163.5.805. PMID: 16648320.Psychiary, No015

⁷ Kemény LV, Robinson KC, Hermann AL, Walker DM, Regan S, Yew YW, Lai YC, Theodosakis N, Rivera PD, Ding W, Yang L, Beyer T, Loh YE, Lo JA, van der Sande AAJ, Sarnie W, Kotler D, Hsiao JJ, Su MY, Kato S, Kotler J, Bilbo SD, Chopra V, Salomon MP, Shen S, Hoon DSB, Asgari MM, Wakeman SE, Nestler EJ, Fisher DE. Vitamin D deficiency exacerbates UV/endorphin and opioid addiction. Sci Adv. 2021 Jun 11;7(24):eabe4577. doi: 10.1126/sciadv.abe4577. PMID: 34117054; PMCID: PMC8195487.

⁸ Jayedi A, Rashidy-Pour A, Shab-Bidar S. Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response †. Nutr Neurosci. 2019 Nov;22(11):750-759. doi: 10.1080/1028415X.2018.1436639. Epub 2018 Feb 15. PMID: 29447107

⁹ Chai B, Gao F, Wu R, Dong T, Gu C, Lin Q, Zhang Y. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol. 2019 Nov 13;19(1):284. doi: 10.1186/s12883-019-1500-6. PMID: 31722673; PMCID: PMC6854782.

10 Jia J, Hu J, Huo X, Miao R, Zhang Y, Ma F. Effects of vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer’s disease: a randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2019 Dec;90(12):1347-1352. doi: 10.1136/jnnp-2018-320199. Epub 2019 Jul 11. PMID: 31296588.

11 Feart C, Helmer C, Merle B, Herrmann FR, Annweiler C, Dartigues JF, Delcourt C, Samieri C. Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer’s disease in older adults. Alzheimers Dement. 2017 Nov;13(11):1207-1216. doi: 10.1016/j.jalz.2017.03.003. Epub 2017 May 16. PMID: 28522216.

12 Ghahremani M, Smith EE, Chen HY, Creese B, Goodarzi Z, Ismail Z. Vitamin D supplementation and incident dementia: Effects of sex, APOE, and baseline cognitive status. Alzheimers Dement (Amst). 2023 Mar 1;15(1):e12404. doi: 10.1002/dad2.12404. PMID: 36874594; PMCID: PMC9976297.

13 Marek K, Cichoń N, Saluk-Bijak J, Bijak M, Miller E. The Role of Vitamin D in Stroke Prevention and the Effects of Its Supplementation for Post-Stroke Rehabilitation: A Narrative Review. Nutrients. 2022 Jul 4;14(13):2761. doi: 10.3390/nu14132761. PMID: 35807941; PMCID: PMC9268813.

14 Wang Z, Ding R, Wang J. The Association between Vitamin D Status and Autism Spectrum Disorder (ASD): A Systematic Review and Meta-Analysis. Nutrients. 2020 Dec 29;13(1):86. doi: 10.3390/nu13010086. PMID: 33383952; PMCID: PMC7824115.

15 Patrick RP, Ames BN. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J. 2015 Jun;29(6):2207-22. doi: 10.1096/fj.14-268342. Epub 2015 Feb 24. PMID: 25713056.

16 Sonia L Robinson, Constanza Marín, Henry Oliveros, Mercedes Mora-Plazas, Betsy Lozoff, Eduardo Villamor, Vitamin D Deficiency in Middle Childhood Is Related to Behavior Problems in Adolescence, The Journal of Nutrition, Volume 150, Issue 1,

2020, Pages 140-148, ISSN 0022-3166, https://doi.org/10.1093/jn/nxz185.

17 Hemamy M, Pahlavani N, Amanollahi A, Islam SMS, McVicar J, Askari G, Malekahmadi M. The effect of vitamin D and magnesium supplementation on the mental health status of attention-deficit hyperactive children: a randomized controlled trial. BMC Pediatr. 2021 Apr 17;21(1):178. doi: 10.1186/s12887-021-02631-1. Erratum in: BMC Pediatr. 2021 May 12;21(1):230. PMID: 33865361; PMCID: PMC8052751.

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Both brain size and IQ are falling in modern humans, coinciding with a big increase in mental illness.

What we eat is to blame, says Professor Michael Crawford, author of a new book ‘The Shrinking Brain’ and Sir David Attenborough is convinced he is right.

The Falling IQ

IQ scores have also been steadily falling for the past few decades. Norwegian researchers, headed by Ole Rogeberg, a senior research fellow at the Ragnar Frisch Center for Economic Research in Norway, analysed the IQ scores of Norwegian men born between 1962 and 1991 and found that scores steadily decreased among those born after 1975 (1). “Similar studies in Denmark, Britain, France, the Netherlands, Finland and Estonia have demonstrated a similar downward trend in IQ scores” says Rogeberg. “The decline is due to environmental factors,” 

This coincides with a change in Western diet away from fat, towards carbohydrates and sugar, based on the mistaken belief that it was fat, not sugar, that was causing heart disease and that we should all eat a low-fat diet. Since then, our IQ scores have been dropping by about 7 per cent per generation. 

“We are heading for an idiocracy” says Professor Crawford who is Director of the Institute of Brain Chemistry and Human Nutrition. Currently one in five of the world’s children and adolescents have a mental health condition (2).’  If this trend continues, by 2080 he predicts that more than a third of the world’s population will have a mental disability.

The World Health Organisation report says ‘there has been a 13% rise in mental health conditions. One in eight now suffers from mental illness. The incidence of depression is through the roof. Last year in the UK there were over 100 million prescriptions for antidepressants. 

Crawford is convinced it is the modern-day diet that is causing us to dumb down. “Our genome is adapted to eating the wild foods we ate during our species’ evolution. Today’s diet bears no resemblance to this.”

Key nutrients from land & sea

In his book, The Shrinking Brain, he says “Our ancestors evolved a unique 1,600cc brain evolving from our ancestral 350cc brain of the chimpanzee, despite our genome only differing by 1.5% (3). This could only have happened by providing brain-specific building nutrients from land and sea. There is incontrovertible evidence of early Homo sapiens exploiting the marine food web in coastal Africa.” In other words, we were the waterside ape who became smart, with bigger brains, by eating mussels, oysters, crabs and fish. 

Professor Crawford discovered, in 1971, that the brains of all mammals are rich in omega-3 DHA. Their brain size varied according to their dietary supply of DHA found in seafood. A dolphin, for example, has a 1,700cc brain, slightly larger than ours, while a lion has a 320cc brain about that of a chimpanzee. “The mix of wildland and aquatic foods powered by the encephalization of the brain from the 340cc of the chimp to the 1,500-1,700 of cro-magnon. DHA is not only involved in signalling but it stimulates gene expression in the brain so the rich aquatic food sources constantly, every day, would have powered the increase in brain size and function.” says Crawford.

“Today’s diet contains less than a tenth of the omega-3 fats that our ancestors ate and this is having dire consequences on mental health. Increased rates of depression, autism, ADHD and dementia are all strongly linked to lack of seafood. Increased intake from eating fish or supplementing omega-3 fish oils reduces dementia risk by 20 per cent (4). While a plant-based diet has many benefits, those who eat no fish, are especially vulnerable and must supplement omega-3 DHA, derived from algae. The only way to be sure you have enough is to get a blood test to specifically test your levels.” Says our CEO and founder Patrick Holford.  

This is why we have just launched a simple ‘do it at home’ pin-prick test that can give you a clear indication of your Omega-3 levels, which done alongside our Cognitive Function Test, can help identify what’s driving future risk and show you how to dementia-proof your diet and lifestyle. 

Canadian neuroscientist and brain expert Professor Stephen Cunnane at the University of Sherbrook in Canada agrees “A shore-based diet, i.e., fish, molluscs, crustaceans, frogs, bird’s eggs and aquatic plants, provides the richest known dietary sources of brain selective nutrients.” says Cunnane. “Change in diet away from marine foods is the likely explanation for this decrease in brain size.”  

Sir David Attenborough, a supporter of the waterside ape theory, agrees “Gathering molluscs is far easier than chasing elephants and wildebeests across the savannah.” 

Children & omega-3

Today, under 5 per cent of children achieve the basic requirement for omega-3 from seafood (5).

Professor Michael Crawford, who is a visiting professor at Imperial College’s Chelsea & Westminster campus and on our Scientific Advisory Board, was part of the team that has recently established that, if a pregnant woman lacks omega-3 DHA she produces a substitute fat, oleic acid, to fill the baby’s brain. But it doesn’t work. Levels of oleic acid in a pregnant woman’s blood predicted preterm birth which carries the highest risk of developmental brain problems and mental deficits in their offspring, as well as a risk of learning and cognitive disabilities. Low omega-3 and B vitamins in mothers increase risk for lower IQ, learning and emotional problems in children (6).

A new study shows that the higher the omega-3 index and DHA, the greater both the brain size and the cognition of older people (7). Brain size predicts cognitive abilities, which is why we have started offering these vital tests – which are both easy and affordable to do at home.

Brain size is worked out from skull capacity. Homo sapiens skulls dating back to 29,000 years ago had a brain capacity of 1,660cc. By 10,000 years ago it was around 1,500cc or 1.5 kilograms. The average brain size today is a fifth smaller, at 1,336cc. Brain size may have started to shrink from 10,000 years ago, coinciding with mankind developing more land-based agriculture and eating less marine food along rivers and coasts.

 So we are inviting you to join our ‘citizen science’ study to track the impact of diet and Omega-3 on cognitive function over time.

Our brains and mental health are suffering as a result of our dietary changes.

So if you are concerned about your levels of Omega-3 and how it might be impacting your brain, body and life – you can now test your levels with our Omega-3 hometest kit here, which is offered alongside the free Cognitive Function Test, which assesses how well your diet is supporting your brain health.

Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

Supporting Research

IQ FALLING

Bratsberg B, Rogeberg O. Flynn effect and its reversal are both environmentally caused. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6674-6678. doi: 10.1073/pnas.1718793115. Epub 2018 Jun 11. PMID: 29891660; PMCID: PMC6042097.

DECREASE IN BRAIN SIZE

Cunnane SC, Crawford MA. Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution. J Hum Evol. 2014 Dec;77:88-98. doi: 10.1016/j.jhevol.2014.05.001. Epub 2014 Jun 11. PMID: 24928072.

MENTAL HEALTH RISING

OMEGA-3 PREDICTS COGNITIVE PROBLEMS IN CHILDREN

Montgomery P, Burton JR, Sewell RP, Spreckelsen TF, Richardson AJ. Low blood long chain omega-3 fatty acids in UK children are associated with poor cognitive performance and behavior: a cross-sectional analysis from the DOLAB study. PLoS One. 2013 Jun 24;8(6):e66697. doi: 10.1371/journal.pone.0066697.

OMEGA-3 PREDICTS RISK FOR DEMENTIA AND COGNITIVE DECLINE

Wei BZ, Li L, Dong CW, Tan CC; Alzheimer’s Disease Neuroimaging Initiative; Xu W. The Relationship of Omega-3 Fatty Acids with Dementia and Cognitive Decline: Evidence from Prospective Cohort Studies of Supplementation, Dietary Intake, and Blood Markers. Am J Clin Nutr. 2023 Jun;117(6):1096-1109. doi: 10.1016/j.ajcnut.2023.04.001. Epub 2023 Apr 5. PMID: 37028557; PMCID: PMC10447496.

OMEGA-3 LEVELS PREDICT BRAIN SIZE IN OLDER PEOPLE

Loong, S.; Barnes, S.; Gatto, N.M.; Chowdhury, S.; Lee, G.J. Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults. Brain Sci.2023,13,1278. https://doi.org/ 10.3390/brainsci13091278 

References

¹ Bratsberg B, Rogeberg O. Flynn effect and its reversal are both environmentally caused. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6674-6678. doi: 10.1073/pnas.1718793115. Epub 2018 Jun 11. PMID: 29891660; PMCID: PMC6042097.

² https://www.who.int/publications/i/item/9789240049338

³ Cunnane SC, Crawford MA. Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution. J Hum Evol. 2014 Dec;77:88-98. doi: 10.1016/j.jhevol.2014.05.001. Epub 2014 Jun 11. PMID: 24928072.

⁴ Wei BZ, Li L, Dong CW, Tan CC; Alzheimer’s Disease Neuroimaging Initiative; Xu W. The Relationship of Omega-3 Fatty Acids with Dementia and Cognitive Decline: Evidence from Prospective Cohort Studies of Supplementation, Dietary Intake, and Blood Markers. Am J Clin Nutr. 2023 Jun;117(6):1096-1109. doi: 10.1016/j.ajcnut.2023.04.001. Epub 2023 Apr 5. PMID: 37028557; PMCID: PMC10447496.

⁵ Kranz, S.; Jones, N.R.V.; Monsivais, P. Intake Levels of Fish in the UK Paediatric Population. Nutrients 2017, 9, 392. https://doi.org/10.3390/nu9040392

⁶ Montgomery P, Burton JR, Sewell RP, Spreckelsen TF, Richardson AJ. Low blood long chain omega-3 fatty acids in UK children are associated with poor cognitive performance and behavior: a cross-sectional analysis from the DOLAB study. PLoS One. 2013 Jun 24;8(6):e66697. doi: 10.1371/journal.pone.0066697. Erratum in: PLoS One. 2013;8(9); see also Veena SR, Krishnaveni GV, Srinivasan K, Wills AK, Muthayya S, Kurpad AV, Yajnik CS, Fall CH. Higher maternal plasma folate but not vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9- to 10- year-old children in South India. J Nutr. 2010 May;140(5):1014-22. doi: 10.3945/jn.109.118075. Epub 2010 Mar 24. PMID: 20335637; PMCID: PMC3672847; see also McNulty H, Rollins M, Cassidy T, Caffrey A, Marshall B, Dornan J, McLaughlin M, McNulty BA, Ward M, Strain JJ, Molloy AM, Lees-Murdock DJ, Walsh CP, Pentieva K. Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT Offspring Trial). BMC Med. 2019 Oct 31;17(1):196. doi: 10.1186/s12916-019-1432-4. PMID: 31672132; PMCID: PMC6823954.

⁷ Loong, S.; Barnes, S.; Gatto, N.M.; Chowdhury, S.; Lee, G.J. Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults. Brain Sci.2023,13,1278. https://doi.org/ 10.3390/brainsci13091278 

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How does our ‘do it at home’ pinprick blood test for omega-3 predict your cognitive ability, dementia risk, brain size and intelligence? 

We are a charity dedicated to researching cognitive function and helping people look after their brain and reduce their risk of dementia and other brain-related health challenges, and TODAY we have launched a new ‘do it at home’ pinprick blood test for omega-3.

Multiple studies, including a new study, by psychologists at the Linda Loma University in California and published in the journal Brain Sciences (1), have found that the higher a person’s omega-3 index was in their blood, the more white matter there was in their brain, and the better they performed on cognitive tests that predict less risk for dementia.

With omega-3 such an important brain-health indicator, we have launched an easy, do it yourself, home pin prick test, so your omega-3 levels can be accurately determined. 

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Research also shows that the test can predict brain size and cognitive function. 

The study in California not only found omega-3 was a clear predictor of cognitive function and dementia risk (the higher the omega-3, the lower the risk), it also found that in older people in good health, levels of omega-3 predicted both their brain volume and their cognitive abilities on tests of memory and speed of thinking (the higher the level the bigger their brain volume and the faster their thinking).

“This confirms previous growing evidence that a person’s omega-3 index, which is a composite score of the two main brain-friendly omega-3 fats found in seafood, called EPA and DHA, predicts both the risk for depression (2) and dementia (3), and poorer reading ability, lower IQ, worse memory, difficulty sleeping, aggression and emotional instability in children – hallmarks of ADHD (4) .” says Patrick Holford, our founder and CEO.

The Omega-3 index, which should be above 8%, also predicts risk for heart disease (5) and developmental problems in babies from measures taken in women both before and during pregnancy. “Pregnant women with a higher omega-3 index have a much lower risk of having a baby with developmental problems, according to research at Imperial College London from the Institute of Brain Chemistry at the Chelsea & Westminster Hospital campus.” adds Holford. “It is wise for a woman considering pregnancy to check their omega-3 index and ensure it is above 8%.”

The home test kit, now available HERE also includes our free Cognitive Function Test and a questionnaire to complete about your diet and lifestyle that then identifies the key changes that lower risk of dementia. 

We have tested over 400,000 people and our goal is now to track people’s blood levels of omega-3 with cognitive function to work out exactly what the optimal intake of omega-3 for brain health actually is – so we need your help!

What about Omega-3 from plants?

While there is a type of omega-3 fat (called linolenic acid) in green leafy vegetables, as well as walnuts, chia and flax seeds, its conversion into EPA and DHA is poor. The ability to convert plant-based omega-3 into EPA, which is associated with better mood, and DHA which is the main brain-building omega-3 fat linked to lower risk of age-related memory decline and dementia, varies from person to person. So we hope to find out whether other factors such as age, sex, alcohol consumption and dietary habits, other than seafood intake, make a difference to the ability to make the brain-friendly types of omega-3 measured in this test.

The intake of marine foods has continued to decline over the past hundred years and countries with the lowest intake have the most risk for depression (6), dementia (7) and suicide (8). Even the rate of homicide is linked to a country’s omega-3 intake according to World Health Organisation data (9). 

Less than 5 per cent of children achieve the basic government guidelines for eating fish and omega-3 (10) however we really don’t know if even these guidelines are optimal for mental health. So the more people who are willing to take this inexpensive test and complete a short questionnaire about their dietary habits, plus take a 10-minute online Cognitive Function Test, the more effectively we can discover what an optimal intake of omega-3 for brain health and the prevention of dementia later in life is.

So will you join us and become citizen scientists in this way and help us advance this much-needed area of research – while also helping improve your own brain health?

The test, which costs £49.95, helps to support this research, so to check your omega-3 status click here.

Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

References

¹ Loong, S.; Barnes, S.; Gatto, N.M.; Chowdhury, S.; Lee, G.J. Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults. Brain Sci.2023,13,1278. https://doi.org/ 10.3390/brainsci13091278 

² Yonezawa K, Kusumoto Y, Kanchi N, Kinoshita H, Kanegae S, Yamaguchi N, Ozawa H. Recent trends in mental illness and omega-3 fatty acids. J Neural Transm (Vienna). 2020 Nov;127(11):1491-1499. doi: 10.1007/s00702-020-02212-z. Epub 2020 May 25. PMID: 32451632.

³ Wei BZ, Li L, Dong CW, Tan CC; Alzheimer’s Disease Neuroimaging Initiative; Xu W. The Relationship of Omega-3 Fatty Acids with Dementia and Cognitive Decline: Evidence from Prospective Cohort Studies of Supplementation, Dietary Intake, and Blood Markers. Am J Clin Nutr. 2023 Jun;117(6):1096-1109. doi: 10.1016/j.ajcnut.2023.04.001. Epub 2023 Apr 5. PMID: 37028557; PMCID: PMC10447496.

⁴ Montgomery P, Burton JR, Sewell RP, Spreckelsen TF, Richardson AJ. Low blood long chain omega-3 fatty acids in UK children are associated with poor cognitive performance and behavior: a cross-sectional analysis from the DOLAB study. PLoS One. 2013 Jun 24;8(6):e66697. doi: 10.1371/journal.pone.0066697. Erratum in: PLoS One. 2013;8(9).doi:10.1371/annotation/26c6b13f-b83a-4a3f-978a-c09d8ccf1ae2. PMID: 23826114; PMCID: PMC3691187; see also Raine A, Ang RP, Choy O, Hibbeln JR, Ho RM, Lim CG, Lim-Ashworth NSJ, Ling S, Liu JCJ, Ooi YP, Tan YR, Fung DSS. Omega-3 (ω-3) and social skills interventions for reactive aggression and childhood externalizing behavior problems: a randomized, stratified, double-blind, placebo-controlled, factorial trial. Psychol Med. 2019 Jan;49(2):335-344. Doi 10.1007/s11920-018-0894-y. PMID: 29623453. ; see also Liu, J., Cui, Y., Li, L. et al. The mediating role of sleep in the fish consumption – cognitive functioning relationship: a cohort study. Sci Rep 7, 17961 (2017). https://doi.org/10.1038/s41598-017-17520-w

⁵ 1 Elagizi A, Lavie CJ, O’Keefe E, Marshall K, O’Keefe JH, Milani RV. An Update on Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Health. Nutrients. 2021 Jan 12;13(1):204. doi: 10.3390/nu13010204. PMID: 33445534; PMCID: PMC7827286.

⁷ Yonezawa K, Kusumoto Y, Kanchi N, Kinoshita H, Kanegae S, Yamaguchi N, Ozawa H. Recent trends in mental illness and omega-3 fatty acids. J Neural Transm (Vienna). 2020 Nov;127(11):1491-1499. doi: 10.1007/s00702-020-02212-z. Epub 2020 May 25. PMID: 32451632.

⁸ Hibbeln JR. Depression, suicide and deficiencies of omega-3 essential fatty acids in modern diets. World Rev Nutr Diet. 2009;99:17-30. doi: 10.1159/000192992. Epub 2009 Jan 9. PMID: 19136836.

⁹ Hibbeln JR. From homicide to happiness–a commentary on omega-3 fatty acids in human society. Cleave Award Lecture. Nutr Health. 2007;19(1-2):9-19. doi: 10.1177/026010600701900204. PMID: 18309762.

¹⁰ Kranz, S.; Jones, N.R.V.; Monsivais, P. Intake Levels of Fish in the UK Paediatric Population. Nutrients 2017, 9, 392. https://doi.org/10.3390/nu9040392

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.

By Patrick Holford

What does any animal, perhaps your dog, do after exercising or going for a walk?

Sleep. 

Sleep is how the brain recovers. There is now overwhelming evidence that sleep is a ‘brain essential’ and just like Goldilocks, it seems we need just the right amount. Getting too much, or too little, increases our risk for cognitive decline.

If you want to put a number on it, it appears the optimal amount of sleep for brain health is seven hours in total. And, for the light sleepers among us, there is some debate about whether it needs to all be in one go – one study found that a nap after physical exercise was in fact good for the brain, reducing the risk of cognitive impairment. 

However, for those of us with problems sleeping, or who get consistently less than the recommended seven hours, we may be literally doubling our risk of age-related cognitive decline. A UK study of Whitehall civil servants, started in the 1980’s, examining their health from the age of 35 and onwards found that ‘persistent short sleep duration at age 50, 60, and 70 compared to persistent normal sleep duration was also associated with a 30% increased dementia risk’. But it’s not just future risk of dementia that lack of sleep cranks up: it’s our ability to function the next day and to feel good. Lack of sleep decreases empathy and increases negative emotions.

Why do we sleep and why is it essential to the brain? 

Sleep can be thought of as the brain’s housekeeper. During sleep, blood and cerebrospinal fluid circulation improves, and waste products of brain metabolism get removed. These waste products include both oxidants and amyloid protein, associated with Alzheimer’s and brain inflammation, which starts to accumulate after just one night of sleep deprivation. That’s a big reason your brain needs this downtime.

One of the key powerhouses that helps clean up our brains while we sleep is melatonin. So why doesn’t melatonin do this all the time? As nightfall approaches, our brains convert serotonin into melatonin. Deep in the centre of our brain – the centre of our soul according to the philosopher Descartes, or the ‘third eye’ chakra in Yoga – melatonin is made in the pineal gland. Sensitive to light, most likely through receptors at the back of our eyes, the pineal is the only endocrine gland in contact with the outside world. Darkness stimulates the production of melatonin, whereas exposure to light (cue that late night phone scrolling!) suppresses production. 

Melatonin, then, keeps us ‘in sync’ with the day/night cycle. (Indeed, some frequent flyers find that taking melatonin supplements can help them adjust more quickly to a new time zone and avoid the tired-all-day feeling of jet lag and give them a better night’s sleep.)

Increasing levels of melatonin help us fall asleep and keep us asleep, so what is melatonin actually doing? 

Although there are many by-products of the day’s brain activity, one big slice of the toxins that accumulate in the brain are various oxidants. Apart from all the antioxidants and polyphenols we can eat to keep our brains young, melatonin is perhaps the most important antioxidant helping to disarm these oxidants and restore the mitochondrial energy factories to full function. 

Melatonin is made from a type of tryptophan, 5-HTP, a potent antidepressant. Melatonin is also a powerful anti-inflammatory and supplementation has been used to speed up recovery from cancer, covid and cardiovascular disease.

Melatonin, then, is crucial for brain health and sleep routine, and a loss of this natural circadian rhythm, and lower brain levels of melatonin are found in those with cognitive decline. 

Why dreaming is important

But there’s something else going on while we sleep, and particularly as we dream, that supports brain health. 

All being well, after about 30 minutes, we enter a period of deep sleep when our heart rate reduces, our blood pressure drops and our breathing becomes slower. This is the most restorative stage of sleep when tissue repair and regeneration occurs. After around 90 minutes, we then shift to a period of REM (rapid-eye-movement) sleep, which is when most dreaming occurs. As far as the brain is concerned, the most critical phases of sleep are these bursts of REM sleep. Lasting about 30 minutes, we move back and forth between deep sleep, lighter sleep and REM,on average between three to five times a night, with the REM stage ideally accounting for around 25% of our overall sleep time.

During the night, and especially during the deep and REM sleep phases, our brains also produce higher levels of growth hormone. This hormone helps with the repair and regeneration of our body’s tissues while melatonin helps clear out the waste products of metabolism. 

However, when we are stressed, high levels of the stress hormone cortisol suppress REM sleep and growth hormone production, diverting energy away from repair, and effectively speeding up the brain’s ageing process. In fact, people who are deprived of REM sleep won’t feel fully rested on waking and in turn are more likely to get depressed. When they do get a chance to sleep, they will often have longer periods of REM sleep, of which suggests that our brains need this time while we’re asleep to process what’s been happening in our lives. One theory is that negative emotions such as anger, fear, sadness, or frustration, often suppressed in our hectic lifestyles or the modern workplace, can be experienced and released during dreaming. To test this theory, when we have a strong negative emotion in a dream, it’s useful to track back to our experiences the day before when we felt a similar emotion.

Stress ages your brain

A good night’s sleep might help us process a bad day at the office, major stress, or prolonged anxiety, stress or overwhelm, age the brain and increase our risk of cognitive decline and dementia in the future. This has been shown by tracking people who have had two or more major stressful events such as death of a spouse, child or grandchild, divorce, financial or health problems, but also perceived psychological stress in adulthood and levels of neuroticism. 

Stress is also linked to our perception of control in our lives. One study assessed people’s work based on two criteria: how demanding the job was and how much control the person had. Those who did worse both for depression and cognitive decline had both high demands and low control over the circumstances. For example, a classic example of high stress might be caring for a parent with dementia and dealing with various NHS and social service bureaucracies. Another would be a stressful job where you don’t have the power, or the budget, to make necessary changes. Having too many unfinished things is also a classic source of overwhelm. 

But what is stress actually doing to our brain?

 The best way to understand this is to talk about the two main stress hormones, Adrenaline and Cortisol, both essential for keeping us safe and alive. Adrenalin is short-acting, kicking in, in under a second and lasting for up to an hour (but usually less). It’s what we needed to get away from the sabre-toothed tiger, or feel ready to take on a sporting challenge or that big presentation. Cortisol, on the other hand, is long acting and its level cycles throughout the day. In the morning, cortisol levels rise to kick start our day and in the evening, as we approach sleep, our cortisol levels should be reducing. But if our cortisol level is high at night we’ll have difficulty getting to sleep and if it’s low in the morning, we’ll be reaching for the caffeine before we’ve opened our eyes. 

At an evolutionary level, our ‘stress’ reaction is vital to our survival..  

However, when we get stuck in reacting stressfully, sleeping poorly or waking up with stressful thoughts, and operating with a background level of anxiety, we end up with continuous elevated cortisol as a result. This is bad news as excess cortisol is linked by many studies with worsening overall cognitive functioning, memory, slower thinking and poorer social skills, and ultimately, a greater risk of dementia and Alzheimer’s in our later years.   

What’s actually going on in the brain is that cortisol triggers these stress responses in the limbic brain which includes the hippocampus. This part of the brain then feeds back to put the brakes on further cortisol release. But, with prolonged stress, or anything else that triggers hippocampal shrinkage, the brakes on cortisol don’t get fully applied so you get into a negative loop of continued cortisol leading to increased hippocampal brain shrinkage. 

The negative loop of sugar, alcohol and stress

But this isn’t the only negative feedback chemical keeping us stressed out and stuck.  The psychologist and philosopher Oscar Ichazo uses the term ‘doors of compensation’ to describe those things we reach for when we’re stressed, and not all of them are good. 

Drinking alcohol, smoking or taking drugs, and sugar are common choices to make us feel better in the short term but the long-term effect is anything but. . 

 Alcohol, for example, causes an immediate increase in the calming neurotransmitter GABA, which also switches off adrenalin – at least for an hour or so. But there are two main problems with this. Firstly, the effect wears off and drinking too much in the evening actually shuts down GABA receptors the next day, cue the negative cycle of feeling more anxious and more stressed. The second is that alcohol is a neurotoxin and, ultimately, contributes to a brain downgrade, increasing the risk of dementia. It also negatively impacts the quality of our sleep, as the brain ‘shuts down’ rather than getting on with the vital repair and regeneration it needs during those vital hours of shut eye. 

Another favourite ‘door of compensation’, especially among those who don’t drink, is sugar.

 This is partly because of the ‘feel good’ effect of glucose, stimulating the brain’s reward system but, which in excess, leads us to continue to crave sugar more and more.  But what makes the combo of sugar and stress particularly insidious is that glucose cranks up the adrenal system, magnifying the response to stress and corresponding cortisol levels. Just in case you’re wondering, other foods high in protein or fat don’t do this. It is specifically sugar or glucose.

We routinely ‘cope’ with stress by drinking alcohol or eating sugar or both then, the likelihood is that, the next day we’ll feel more dopey and anxious or stressed on waking due to the lack of GABA receptors and lower blood sugar levels. Invariably, we are more inclined to reach for that morning cuppa Joe – a caffeinated drink and something sweet to eat. This then sets you up for more cortisol release, which makes us more stressed so, by the evening, we need more alcohol. This combo increasingly shrinks our hippocampus, the part of the brain which gives the feedback signal to switch off cortisol. Result? We live in a constant state of stress. This is a cycle we need to get out of.

The good news is, it’s possible to reverse the cycle, and start feeling good.

Here are some some simple steps to support your brain and feel better:

Focus on your sleep. Are you getting at least 7 hours a night? 
What regularly stresses you out? How could it be reduced?
Are you mindful of your alcohol and sugar intake? 
Can you find some positive ‘doors of compensation’, like gentle yoga, or a good book?
Complete the Cognitive Function Test to assess your brain health and then join COGNITION to get personalised recommendations so that you can reclaim your brain over the next 6 months.

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And if you want to get more support and more tools on how to deal with stress and support, then make sure you join us in our next webinar.

Solving Anxiety: How to Identify Your Individual Triggers and Find Resolution is on Thursday 19th October 

Click here to find out more

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Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

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References:

¹ Qian YX, Ma QH, Sun HP, Xu Y, Pan CW. Combined effect of three common lifestyle factors on cognitive impairment among older Chinese adults: a community-based, cross-sectional survey. Psychogeriatrics. 2020 Nov;20(6):844-849. doi: 10.1111/psyg.12604. Epub 2020 Aug 31. PMID: 32869429.

² Bubu OM, Brannick M, Mortimer J, Umasabor-Bubu O, Sebastião YV, Wen Y, Schwartz S, Borenstein AR, Wu Y, Morgan D, Anderson WM. Sleep, Cognitive impairment, and Alzheimer’s disease: A Systematic Review and Meta-Analysis. Sleep. 2017 Jan 1;40(1). doi: 10.1093/sleep/zsw032. PMID: 28364458.

³ Sabia S, Fayosse A, Dumurgier J, van Hees VT, Paquet C, Sommerlad A, Kivimäki M, Dugravot A, Singh-Manoux A. Association of sleep duration in middle and old age with incidence of dementia. Nat Commun. 2021 Apr 20;12(1):2289. doi: 10.1038/s41467-021-22354-2. PMID: 33879784; PMCID: PMC8058039.

⁴ Krause AJ, Simon EB, Mander BA, Greer SM, Saletin JM, Goldstein-Piekarski AN, Walker MP. The sleep-deprived human brain. Nat Rev Neurosci. 2017 Jul;18(7):404-418. doi: 10.1038/nrn.2017.55. Epub 2017 May 18. PMID: 28515433; PMCID: PMC6143346.

⁵ Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520. doi: 10.1002/14651858.CD001520. PMID: 12076414.

⁶ Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224. PMID: 24136970; PMCID: PMC3880190.

⁷ Shokri-Kojori E, Wang GJ, Wiers CE, Demiral SB, Guo M, Kim SW, Lindgren E, Ramirez V, Zehra A, Freeman C, Miller G, Manza P, Srivastava T, De Santi S, Tomasi D, Benveniste H, Volkow ND. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):4483-4488. doi: 10.1073/pnas.1721694115. Epub 2018 Apr 9. PMID: 29632177; PMCID: PMC5924922.

⁸ Keithahn C, Lerchl A. 5-hydroxytryptophan is a more potent in vitro hydroxyl radical scavenger than melatonin or vitamin C. J Pineal Res. 2005 Jan;38(1):62-6. doi: 10.1111/j.1600-079X.2004.00177.x. PMID: 15617538.

⁹ Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, Zagrean AM. Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules. 2020 Aug 20;10(9):1211. doi: 10.3390/biom10091211. PMID: 32825327; PMCID: PMC7563541; regarding covid see also Tan DX, Reiter RJ. Mechanisms and clinical evidence to support melatonin’s use in severe COVID-19 patients to lower mortality. Life Sci. 2022 Apr 1;294:120368. doi: 10.1016/j.lfs.2022.120368. Epub 2022 Jan 30. PMID: 35108568; PMCID: PMC8800937.; see also Begum R, Mamun-Or-Rashid ANM, Lucy TT, Pramanik MK, Sil BK, Mukerjee N, Tagde P, Yagi M, Yonei Y. Potential Therapeutic Approach of Melatonin against Omicron and Some Other Variants of SARS-CoV-2. Molecules. 2022 Oct 16;27(20):6934. doi: 10.3390/molecules27206934. PMID: 36296527; PMCID: PMC9609612.; regarding cancer see Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci. 2017 Apr 17;18(4):843. doi: 10.3390/ijms18040843. PMID: 28420185; PMCID: PMC5412427.

¹0 Franks KH, Bransby L, Saling MM, Pase MP. Association of Stress with Risk of Dementia and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2021;82(4):1573-1590. doi: 10.3233/JAD-210094. PMID: 34366334.

¹1 Wang HX, Wahlberg M, Karp A, Winblad B, Fratiglioni L. Psychosocial stress at work is associated with increased dementia risk in late life. Alzheimers Dement. 2012;8(2):114-20. doi: 10.1016/j.jalz.2011.03.001. PMID: 22404853; see also Gonzalez-Mulé, E., & Cockburn, B. S. (2021). This job is (literally) killing me: A moderated-mediated model linking work characteristics to mortality. Journal of Applied Psychology, 106(1), 140–151. https://doi.org/10.1037/apl0000501; see also Gonzalez-Mulé E, Kim MM, Ryu JW. A meta-analytic test of multiplicative and additive models of job demands, resources, and stress. J Appl Psychol. 2021 Sep;106(9):1391-1411. doi: 10.1037/apl0000840. Epub 2020 Sep 21. PMID: 32955269.

¹2 Ouanes S, Popp J. High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature. Front Aging Neurosci. 2019 Mar 1;11:43. doi: 10.3389/fnagi.2019.00043. PMID: 30881301; PMCID: PMC6405479.

¹3 Gonzalez-Bono E, Rohleder N, Hellhammer DH, Salvador A, Kirschbaum C. Glucose but not protein or fat load amplifies the cortisol response to psychosocial stress. Horm Behav. 2002 May;41(3):328-33. doi: 10.1006/hbeh.2002.1766. PMID: 11971667.

Developing dementia is the second biggest health fear, after cancer. But what can you do about it? 

The conventional view is that genes play a big part and that factors under our control, including diet, lifestyle and health status, account for up to 40% of risk and therefore up to 40% of dementia cases could be prevented or delayed. Genes actually account for less than 1% of Alzheimer’s cases. But a new study from the UK BioBank, following 344,000 people over 15 years, estimates that “up to 73% of cases could be prevented” by targeting risk factors largely under our control. 

The authors of the study, published in the Nature Human Behaviour journal (1), investigated 210 modifiable risk factors. They found that increased hand grip strength (a good reflection of physical strength), increasing leisure or social activities or time spent in sports clubs or gyms, spending less time watching TV or on a computer, having better dental health, drinking more water, not dozing off in the day and sleeping between 7 to 9 hours a night, not smoking or being exposed to smoke and having better lung function were all associated with less risk of Alzheimer’s. Being unemployed, having a low income, having diabetes, high blood pressure or having had a stroke or brain injury all increased risk. Inheriting the so-called ‘Alzheimer’s gene’, ApoE4, didn’t make any significant difference to overall risk.

However, even this figure of 73% may be an underestimate as this study excluded blood test measures. “We have under-estimated the power of prevention,” says Professor David Smith from the University of Oxford, one of the study authors. “Even this figure of up to 73% of cases preventable could be higher if a person’s omega-3 and B vitamin status, measured by a blood test for homocysteine that any GP can do, were taken into account.”

While the BioBank study didn’t include blood test measures of either homocysteine or omega-3, scientists at the US National Institutes of Health have attributed 22% of the risk of Alzheimer’s to raised blood homocysteine and 22% to a lack of omega-3 (2). “These have been shown to predict risk but were beyond the scope of this study.” confirmed the study author, Professor Jin-Tai Yu from Shanghai’s Fudan University. “Homocysteine-lowering treatment with B vitamins, especially B12, is one of the most promising interventions for dementia prevention.” 

The Impact of B Vitamins & Omega-3

Professor Smith’s group at Oxford University tested the effects of giving B vitamins (B6, B12, folate) versus placebo to those with pre-dementia and found that the 10p a day supplements halved the rate of brain shrinkage in one year and virtually stopped further memory loss (3). “The greatest effect we found in our trial was in those in the top third of DHA blood levels (an omega-3 found in fish or fish oil supplements). Those with high DHA reduced their rate of brain shrinkage by 73%, down to the level normally seen in older people with loss of cognitive function. They also had virtually no further memory loss and almost a third ended the trial with no clinical dementia rating at all.”

The benefit of omega-3 was also confirmed in a major study this year of over 100,000 people, finding that increased omega-3 cut the risk of dementia or cognitive decline by around 20%. An increase in intake of omega-3 DHA of 200 mg decreased risk by almost a fifth (4). 

And here at Food for the Brain, we take prevention seriously.

Alzheimer’s is preventable, but not curable

We developed the free online Cognitive Function Test,  which includes a Dementia Risk Index questionnaire assessing your diet, omega-3 and B vitamin status, and lifestyle and an optional home-test kit for pinprick blood tests that will be available soon.

“Over 400,000 people have taken our validated Cognitive Function Test, which not only shows a person their cognitive status right now but also their future risk based on our Dementia Risk Index questionnaire, the factors driving future risk and what they can easily do right now to lower it. If all modifiable risk factors are taken into account, including B vitamins and omega-3, it is highly likely a person could reduce risk by over 80%.” says our CEO, Patrick Holford.

“The government has pledged £160 million a year for dementia prevention research but we are not seeing any of this going into easy prevention wins. Most seem to be fueling drug research for an apparent ‘cure’.

Alzheimer’s is preventable, but not curable. You cannot reverse holes in the brain. With over 200,000 people diagnosed every year with dementia, if prevention were taken seriously we could halve the number of people developing this terrible, but preventable disease.”

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Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

———

References

¹ Zhang, Y., et al. Nature Human Behaviour. 2023 7, 1185–1195

² Beydoun MA., et al. BMC Public Health. 2014 Jun 24;14:643.

 Jernerén F., et al. Am J Clin Nutr. 2015 Jul;102(1):215-21.

³ Oulhaj A., et al. J Alzheimers Dis. 2016;50(2):547-57.

⁴ Wei B., et al. Am J Clin Nutr 2023 Jun;117(6):1096-1109. 

Keeping our brain’s structure and neural network healthy may seem like a mystery at times, but often the best advice is simple: ‘use it or lose it!’

The exercise and stimulation your brain gets from an active physical, social and intellectual lifestyle is vital to keeping it healthy. Just like our bodies need movement and exercise to function well, our brains need their own workout to thrive, too.

Lifestyle expert at Food for the Brain, Assistant Professor Tommy Wood, from the University of Washington has advised people at the top of their game, from Formula 1 drivers and Olympians to world champions, on how to maximise their performance, both mentally and physically.  His top tip for keeping our brains sharp?  

“In short, 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.”

“That’s not necessarily true” says Professor Wood. “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.”

A classic example of this is a study of London taxi drivers in training who have to learn ‘The Knowledge’. Many spend three years driving the 25,000 streets of London, logging up tens of thousands of miles, on foot or on a scooter. Not all pass the first time. Katherine Woollett at University College London decided to find out if acquiring the knowledge actually changed a person’s brain by measuring the density of grey matter as an indicator of brain volume. About half of her group of training taxi drivers passed first time and the other half failed. She also had a control group of people of the same age, most in their late 30’s with similar other demographics such as IQ. Sure enough, those who passed had increased their brain density of grey matter, and specifically in the central hippocampus area most associated with cognitive resilience. (1)

Keep Cognitively Active

There’s a pattern in our society – we are meant to learn every day as we go through school in childhood and teenage years, then we get a job, which, past a training phase, may not require much more learning, then around 65 we are meant to retire, with no more ‘need’ to work or learn.

Every indicator that you can think of – leaving school early, having a lower educational standard (2), or retiring early (3), has been associated with an increasing risk of cognitive decline.

When Professor May Beydoun, at the US National Institutes of Health (NIH) did a comprehensive study of the biggest risk factors for developing Alzheimer’s, she attributed 24% of risk to educational status and 32% of risk to physical activity(4). So, using our brains, reflected in educational and physical activity, is a huge part of keeping your brain healthy. (It’s worth remembering that  omega-3/seafood and homocysteine-lowering B vitamins account for 22% each while smoking racks up 31% in the risk stakes).

Think about how you use your mind. How much time do you spend stimulated, learning something? How much time do you spend engaged in relatively mindless mental activities? 

Television can be stimulating, or mind-numbing – engaging your attention but not really making you think. Social media activity, like scrolling through TikTok or Instagram, could be mind-numbing, while digital engagement with others could be stimulating. A simple yardstick is to ask ‘am I learning anything? Am I using my mind?’ 

While these activities are keeping your brain busy, what our brains really needs is to be engaged in learning or working something out, ideally without too much stress. Many films are designed to engage you by stimulating a stress response, keeping you on the edge of our seat. On the other hand, doing Wordle or a crossword, or playing a game of backgammon or chess involves concentration and thinking without cranking up your stress response. 

Two high-rating apps designed to engage our minds Brain HQ and Lumosity. Brain HQ (www.brainhq.com) adapts according to your needs – do you want better memory, better attention or faster processing? Three 20-minute sessions weekly are recommended. Lumosity (www.lumosity.com) is also adaptive and achieves much the same improvement in cognition. In just the same way you become physically fitter by increasing the duration or intensity of an exercise, it seems the same is true with your mind.

Reading books, or listening to podcasts can also be a great way to stimulate the old grey matter, mind but it does depend on what you are reading or listening to. The golden question is  ‘am I learning anything from this?’. Even better – join a bookclub for the social stimulation, sharing views, hearing others, and working out where you stand. 

Learn by failing

Land on any social media platform and we are bombarded with stories of people succeeding, urging us to try the latest self-help, diet or exercise programme, meditation or music app (who didn’t try and learn the guitar in lockdown!) but failure, according to Professor Tommy Wood, is when the magic really happens for our brains:

“Failure constitutes protective cognitive demand. The cocktail of hormones released as we try, fail, repeat, and learn, provides the ideal environment for the brain to grow and adapt. This is a real sticking point for improving brain health – as adults we hate the feeling of being bad at something.”

Professor Wood recommends picking 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, picking up a guitar is better than listening to music, 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 challenges to keep stimulating your brain.”

“A fascinating study looked at the brains of musicians.  While both professional and amateur musicians’ brains looked younger compared to non-musicians of the same age, the benefit was greatest in amateur musicians (5) – it’s harder, so they got 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.”

In fact, learning an instrument, or a language, are considered heavy lifters when it comes to brain stimulation – it’s challenging and can take a long time to become completely proficient. But every step along the way, even just a few minutes a day, learning new words, processing the grammar, learning chords and finger positions, is a significant mental challenge.  And there are so many language learning apps, like DuoLingo now, playing on the ‘reward’ and game theory to keep us cognitively engaged and coming back for more. 

Speaking two languages is not only associated with less risk of cognitive decline but, according to one study, ‘the neuroprotective effects of lifelong bilingualism act both against neurodegenerative processes and through the modulation of brain networks connectivity.’ (6) Your brain ends up more connected – literally hardwired for brain health.

Keep physically active

The brain also benefits from physical exercise, especially if it involves complex movements and learning – think dance, yoga or t’ai chi or trail running or walking on uneven surfaces. The brain is processing a lot of information, triggering patterns of muscle movement, keeping you in balance. You want a bit of both – movement and balance. Just working out on a fixed machine or walking on a flat, straight, tarmacked path, is not nearly as challenging as hill walking up an uneven path, cycling, surfing, skateboarding or anything where your body is micro-adjusting to keep you in balance.

One study of retired people assigned to walk briskly for 40 minutes three times a week showed increased hippocampal brain volume (7).  Another study showed benefits from doing one or two sessions of resistance or strength training twice a week (8).

Of all the measures relating to how fit or fat we are, muscle mass best predicts brain volume and risk of cognitive decline in later years. 

One big study from the UK Biobank data found that those with a lower fat-to-muscle ratio) in their legs had around 40% less risk for dementia later in life (9). Muscle uses energy and ‘soaks up’ glucose. This helps keep your blood sugar stable and prevent insulin resistance. Often, as we age, it can seem like an uphill battle to keep our weight down, even if we are not eating any more than we used to. This is often simply because we’ve lost muscle mass with age. So hitting those weights can be extra beneficial in later years and many gyms offer classes especially for older clients. Even body weight exercise can build resistance, though, and there are plenty of free videos on the internet – just check with your GP first.

Step it up

A good general guideline is to aim for 30 minutes of brisk walking every day. Some days you may do none and others twice this, so this is a good weekly average to shoot for. Over time you can step it up by walking faster, jogging or including some hills in your circuit. 

A good way to monitor and up our exercise level is to count steps. Smart phones and watches have apps that do this for you. Shoot for increasing daily steps between 10% and 20% a week. If you start at 2,000 and add 200 steps per day each week, that’s a great start. If you’re at 4,000 steps already then getting up to 4,400 daily in this week is also going to stimulate our muscles and brains. While 8,000 steps a day is considered optimal, what’s much more important is to make sustainable improvements as you ‘activate’ your lifestyle.

But, we don’t need to limit ourselves to ‘exercise’. Gardening, mowing the lawn, playing a sport, vigorous cleaning, or clearing out a yard – anything that gives us a faster heart rate, a bit of sweat and engages different sets of muscles, thus including ‘resistance’(10), counts as well, especially if we can do them faster or more energetically.

Aerobic plus resistance exercise anti-ages your brain

As previously mentioned, of all the measures relating to how fit or fat we are, muscle mass best predicts brain volume and risk of cognitive decline in later years. 

Including exercise that helps build and maintain muscle tone correlates most strongly with brain health. A good weekly guideline is to include two resistance training sessions a week. Perhaps you are a member of a gym, go to a pilates or yoga class or have some equipment at home for your own workout.

If you’re not sure where to start, “Burn Fat Fast” (Piatkus, 2013), written by Patrick Holford and exercise guru and former Gladiator (Zodiac) Kate Staples, is a great resource.  Staples devised a series of strength building exercises that anyone can do at home in eight minutes, three times a week, including  beginner version, and intermediate and advanced versions (light to medium weight dumbbells (2kg – 6kg) are needed for these).

The exercises are all explained in the book and  Kate Staples demonstrates each one HERE so you can follow along until you feel comfortable. A five minute warm-up (marching on the spot is great, or stepping side to side) will get your heart rate up and help avoid injury. 

The beginner sequence includes wall sits and reverse lunges, while the advance sequence progresses to jumping squats and mountain climbers. It’s important to build up gradually, keep hydrated, and learn to do the moves safely, so watching the videos is a great way to get started. 

The secret is to find an activity that engages both mind and body, builds muscle, and is not too repetitive. As an example, our very own Patrick Holford says “I’ve taken up paragliding, and qualified at the age of 65. I had to pass an exam on meteorology, aerodynamics and air law, and failed the first time, but now I have to think about these things before and during flight. Then there’s the exercise of carrying an 11 kg pack up a mountain, and the balance and strength and adjustments my brain is having to make to keep the canopy stable even before take off.” This may not be your thing but it shows how one activity can tick so many brain boxes. It is good to learn new sports for this very reason.

Be Social

A lack of meaningful social interaction, and loneliness, is also a major driver of both low mood and cognitive decline later in life (11). 

How often do you go to social gatherings, meet new people and have engaging conversations? This could be meeting friends, going to the movies, a museum, a gallery, a show, church or temple, or a restaurant?

There are times in your lives where you might find yourself more isolated. For example, when relationships break up and you lose connection with ‘their’ friends, or if a partner dies and most of your social interaction was with them. These are extremely challenging times, but facing our fears and getting out there to meet friends can help us on the road to recovery. 

Unset your mind

It’s all too easy to get locked into routines that remove any form of challenging social interaction yet this is not only how we learn, it also nourishes the social aspect of who we are. A good strategy is to make sure you have a significant social event or interaction every week, starting with this week.

As we age, and friends move away, or pass on, it’s important to find ways to expose ourselves to new ideas and new ways of thinking and feeling differently and swapping ideas. Travelling and exploring other cultures can be an incredibly enriching way to broaden our mindset and there are lots of companies that cater for the solo traveller these days.

But there’s no need to go far from home to get the benefits of brain gain. There are many opportunities to ‘use it or lose it’, for example, volunteering at a local garden or school or supporting the local arts club. The brain boost from being out of your comfort zone will reap dividends, whether it’s joining a group of new people, engaging in a new activity you’ve never tried, like drawing, writing or yoga – or even just catching up with old friends you haven’t seen for ages, or striking up a conversation with someone you meet on the daily dog walk.

Local bookshops, art centres, churches or schools can be great sources of information, so check them out. 

Be inquisitive

As Tommy Wood says “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.”

And if you want more personalised information on how you can improve and support your brain through nutrition and lifestyle changes then make sure you complete our Cognitive Function Test. A FREE, online and validated test to assess your current cognitive function and dementia risk and then get a clear plan of action on how you can improve your brain health and score over the next 6 months.

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Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

References:

¹ 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.

² 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.

³ 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; see also 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.

⁴ 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.

⁵ 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.

⁶ 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.

⁷ 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.

⁸ 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.

⁹ Wang W, Luo Y, Zhuang Z, Song Z, Huang N, Li Y, Dong X, Xiao W, Zhao Y, Huang T. Total and regional fat-to-muscle mass ratio and risks of incident all-cause dementia, Alzheimer’s disease, and vascular dementia. J Cachexia Sarcopenia Muscle. 2022 Oct;13(5):2447-2455. doi: 10.1002/jcsm.13054. Epub 2022 Jul 20. PMID: 35856185; PMCID: PMC9530585.

¹⁰0 Gallardo-Gómez D, Del Pozo-Cruz J, Noetel M, Álvarez-Barbosa F, Alfonso-Rosa RM, Del Pozo Cruz B. Optimal dose and type of exercise to improve cognitive function in older adults: A systematic review and bayesian model-based network meta-analysis of RCTs. Ageing Res Rev. 2022 Apr;76:101591. doi: 10.1016/j.arr.2022.101591. Epub 2022 Feb 17. PMID: 35182742.

¹¹1 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.

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Last week a discovery, published in the journal Science, showed that a high level of an abnormal ‘phosphorylated-tau’ protein triggers brain cells to self-destruct. It also gives a vital clue as to how to stop your brain cells dying with specific vitamins.

When cells become largely dysfunctional, they self-destruct. This process in neurons (brain cells) is called ‘necroptosis’. The recent discovery, made by researchers at the UK’s Dementia Research Institute at University College London (1), showed that an abnormal accumulation of a protein called tau that then becomes phosphorylated, making it tangled and dysfunctional, triggers a specific molecule called MEG3 that triggers brain cell death.

“For the first time we get a clue to how and why neurons die in Alzheimer’s disease. There’s been a lot of speculation for 30-40 years, but nobody has been able to pinpoint the mechanisms. It really provides strong evidence it’s this specific suicide pathway.” researcher Prof Bart De Strooper, from the UK’s Dementia Research Institute. told the BBC.

Even before this, too much phosphorylated-tau (abbreviated to p-tau) interferes with the cell’s energy factories (called mitochondria), potentially leading to brain fatigue. The more p-tau accumulates, the greater a person’s risk for cognitive problems and Alzheimer’s dementia. Also, those with memory decline have been shown to have relatively more p-tau to tau protein.

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

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The answer is remarkably simple – a lack of B vitamins and raised blood levels of homocysteine which is an established risk factor for memory decline, measurable in the blood. When levels of B vitamins (B6, B12 and folate) are low, blood levels of homocysteine go up. This activates one enzyme (Cdk5 kinase) that adds the bad ‘p’ to tau and blocks another enzyme (protein phosphatase A2) which removes the dangerous ‘p’ restoring normal tau protein (2)(3).  High homocysteine also damages the tiny blood vessels in the brain, leading to ‘mini strokes’ or transient ischemic attacks (TIAs), which further raise levels of p-tau (4). Homocysteine both raises levels of the dangerous p-tau and can also bind to tau (5), 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 10 mcmol/L. Half of those above 65 have a level of homocysteine higher than this. The easiest way to lower your homocysteine below 10 mcmol/L is to supplement B6, B12 and folate. 

But it’s also good to eat greens and beans that are high in folate. While B12 is only in animal foods – meat, seafood, eggs and milk. While an optimal supplemental intake for a middle-aged person might be 20mg of B6, 10 mcg of B12, and 400 mcg of folate, many older people start to dramatically lose their ability to absorb B12, the absorption of which requires stomach secretions. Antacid ‘PPI’ medication such as omeprazole accelerates this decline, promoting B12 deficiency. And, over four years of use, increases dementia risk by a third (6). Then, as studies show, you might need a lot more B12, such as 500 mcg, to get a little more into your bloodstream, and possibly more supplemental folate, in the region of 500 to 800 mcg.

This is the cheapest, safest and most logical solution to lower p-tau and prevent brain cells from committing suicide. The problem is that these nutrients, invented by nature, cannot be patented. Therefore it is not in the interest of the pharmaceutical industry to research them.

Consequently, drugs are being developed and tested that block the kinase enzyme and activate the phosphatase enzyme (7), which is exactly what the homocysteine-lowering B vitamins do. But, so far, there are no human clinical trials reporting significant benefit. 

On the other hand, trials giving these kinds of doses of B6, B12 and folic acid have shown up to a two-thirds slower rate of brain shrinkage (8) and virtually no further memory loss in those with pre-dementia (9).

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Thank you for reading!
Food for the Brain is a non-for-profit educational and research charity that offers a free Cognitive Function Test and assesses your Dementia Risk Index to be able to advise you on how to dementia-proof your diet and lifestyle.

By completing the Cognitive Function Test you are joining our grassroots research initiative to find out what really works for preventing cognitive decline. We share our ongoing research results with you to help you make brain-friendly choices.

Please support our research by becoming a Friend of Food for the Brain.

———

References

¹ https://www.science.org/doi/10.1126/science.abp9556 Balasu S et al. Science
14 Sep 2023 Vol 381, Issue 6663 pp. 1176-1182 DOI: 10.1126/science.abp9556

² 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.

³ 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 

⁴ 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.

⁵ 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

⁶ Northuis C, Bell E, Lutsey P, George KM, Gottesman RF, Mosley TH, Whitsel EA, Lakshminarayan K. Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study. Neurology. 2023 Aug 9:10.1212/WNL.0000000000207747. doi: 10.1212/WNL.0000000000207747. Epub ahead of print. PMID: 37558503.

⁷ 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

⁸ 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; see also Jernerén F., et al. Am J Clin Nutr. 2015 Jul;102(1):215-21.

⁹ Oulhaj A., et al. J Alzheimers Dis. 2016;50(2):547-57.