Raised Homocysteine Predicts Over 100 Diseases

Is the H Factor still the biggest health breakthrough of the century?

You may have never heard of it, let alone known your ‘H’ score, but in your bloodstream there exists a toxic amino acid, largely a consequence of sub-optimal B vitamin status, which if raised (above 11µmol/L), is associated with an increased risk of over one hundred diseases and accelerates brain shrinkage. It’s called homocysteine and I consider it more important to know than your weight, your glucose, cholesterol, iron or any other marker, especially if you are intending to become pregnant or are over 40, or have any memory, mental health, neurological or cardiovascular concerns.

I first wrote about it in 2003 in my book ‘The H Factor’ describing it as ‘the biggest health breakthrough of the century’.

Reviewing the book ITV’s This Morning doctor Chris Steele said ‘Homocysteine is the new cholesterol. It’s potentially your most important health statistic.’ In Ireland’s Late Late Show I tested the host Pat Kenny and revealed his level to be way too high (above 15µmol/L). It was his wake up call as he was, according to his wife, heading for a heart attack with poor diet and lots of stress, coffee and alcohol, all of which raise homocysteine.

Now, twenty years on, we know that homocysteine is associated with an increased risk of over 100 diseases or adverse outcomes which are listed at the end of this article, including almost all brain and mental health disorders, from childhood to old age, including dementia and Alzheimer’s.

Technically we can call homocysteine a ‘biomarker’ which is the title of a very important paper ‘Homocysteine – from disease biomarker to disease prevention’ by Professors David Smith and Helga Refsum.[1] you are a health professional or nutritional therapist I strongly recommend you read this seminal paper. David Smith is the Emeritus Professor of pharmacology at the University of Oxford, where he was the Deputy Head of the Faculty of Medical Science. Helga Refsum is Professor of nutrition at the University of Oslo in Norway and formerly a professor of pharmacology. Helga could rightly be called the Queen of Homocysteine because her research, more than any other, has really put this vital biomarker on the map. It was her pioneering Hordland study that started back in 1992, measuring homocysteine in 18,000 men and women in Norway and tracking their health and the diseases they did or didn’t develop .that really put homocysteine on the map.

Homocysteine first came to my attention when Dr Kilmer McCully in the US discovered that children who were dying young from heart attacks had really high levels. This was due to a genetic disorder that leads to homocysteine accumulation in the blood, which then damages the arteries. I wrote about this in my first book, The Whole Health Manual, in 1981. So, here we are 40 years later and still few people know about it, far less know their H score and, worse than that, there has been a concerted effort, largely orchestrated by misleading and wrongful science, to keep the lid on it I beleive because there is no patentable drug that lowers homocysteine – only inexpensive vitamins.

What is more, having a level above 11µmol/L is not at all uncommon. If you are over 60 the odds are high –   40% in the US over 60 have an H score of over 11.[2] It’s probably not much different in the UK but all we know is that two in five adults over 61 in the UK have insufficient B12 to prevent accelerated brain shrinkage.[3] In China its much worse – those under 30 or over 60 average a score above 15.[4] It is realistic to assume that over a third of older people have an H score over 11.


What is Homocysteine and Why is it so Important?

Many nutrients in the body do not work in the form you ingest them – that is until they get ‘methylated’. This is true, for example, for folate or folic acid. It has to turn into methylfolate to become biological active. Many vital biochemicals, from adrenalin to insulin, need to be made and broken down – by methylation. Histamine and hormones such as oestrogen are examples. Also toxins, from mercury to arsenic need to be detoxified – by methylation. The genes you’re born can be ‘activated or expressed’ or ‘downregulated’ or turned off. Methylation does that too. Two thirds of all cancers are associated with faulty methylation which messes up gene messaging.

Homocysteine rises if you’re not doing methylation properly. This is because there’s a log jam on the way to making the body’s most important ‘methylator’ called s-adenosyl methionine or SAMe for short. Think of it as the conductor of the methylation orchestra. It’s made from an amino acid you eat – methionine. It’s another example of a food nutrient that doesn’t work until it is methylated. This happens thanks to enzymes dependent on vitamins B6, B12 and folate turning it into SAMe. This animated film at foodforthebrain.org/hcy shows you how:

How does your body and brain juggle and keep all these thousands of biochemicals you need every second in the right balance? It is a veritable biochemcial symphony going on 24/7. That’s what SAMe does, adding on and taking away methyl groups with literally billions of methylation reactions every minute. If your homocysteine level is above 11 you are not doing it right.

At a very simplistic level you could say that a raised homocysteine indicates that you don’t have enough vitamin B6, B12 or folate. These, together with zinc, trimethyl glycine (TMG) and N-acetylcysteine (NAC) are given to lower a high homocysteine level (which is abbreviated to Hcy here on in).

Get Homocysteine Down Before Getting Pregnant

We call Hcy a biomarker, as opposed to a risk factor as we don’t always know if it is actually causing the problem or just associated with it. That’s also where the chicken and egg story starts. Given that these B vitamins lower Hcy its not so surprising to find that many of the diseases that are associated with high Hcy are also associated with low folate or B12. Pregancy problems are a classic example. Above 9 µmol/L risk of miscarriage and pregnancy complications are higher. Even a Hcy level of above 9 in the mother during pregnancy predicts more problems, specifically withdrawn behaviour, anxiety/depression, social problems and aggressive behaviour in their child at age 6.[5]

Raised Hcy is a well know predictor of miscarriage[6] and pregnancy problems[7]. But is it homocysteine or a lack of folate or B12? Similarly, neural tube defects, for example spina bifida, is strongly associated with both lack of folate and raised Hcy. Giving folic acid supplements reduces risk and lower Hcy. Is Hcy a marker for folate deficiency (yes)? Or is folate deficiency a cause for raised Hcy (yes) and is it actually the Hcy that does the damage (probably)? That’s harder to answer but there are a number of ‘toxic’ consequences of raised Hcy such as damaging the arteries and the brain. Also, there are many things that are generally bad for your health – drinking too much alcohol or coffee, smoking, not exercising, being stressed, having diabetes, not sleeping, all of which are associated with higher Hcy. Suffice it to say that there are plenty of advantages in having a H score below 9, and possibly even lower, and no disadvantages – including less risk of dying.

In those with cardiovascular disease having a H score above 20 increases risk of death by almost five times. Every 5 point increase increases risk by a third.[8] A recent report of almost three thousand cardiovascular patients found that risk of death was almost three times higher for those in the top quartile of Hcy (>15.6) compared with those in the lowest quartile  below <9.8.[9]

Protect Your Brain by Lowering Homocysteine

Hcy damages the arteries including blood vessels in the brain. That’s what Dr Kilmer McCully discovered back in 1969 in children with a genetic disorder. A recent study showed that being in the top quarter for Hcy meant 17 times more risk of cerebrovascular damage.[10] But it also cranks up things like p’tau which is a toxic substance known to cause ‘neurofibrilliary tangles’ which are one of the hallmarks of Alzheimer’s that big pharma is trying to develop a drug for. They needn’t bother because lowering Hcy with inexpensive B vitamins  lowers p’tau. [11] It’s just not profitable.

Not surprisingly, if high, Hcy increases the risk of stroke, and giving folate or B12 lowers risk. In this case we can say Hcy is ‘causal’ as in high levels cause things to happen that lead to stroke or dementia and lowering homocysteine stops or very much slows down those things happening, slowing down brain shrinkage and virtually stopping further memory loss. But, as with many diseases, if you’ve already had a stroke or got Alzheimer’s there is little room for improvement.

Homocysteine for Heart Disease and Stroke

While no-one disagrees that high homocysteine predicts risk for heart disease or stroke some dodgy science more than a decade ago, when the full dynamics of homocysteine and B vitamins weren’t known, cast doubt. One such study in Sweden, called NORVIT, apparently showed no effect from giving B vitamins to people who had had a stroke. ‘The homocysteine hypothesis is dead. Homocysteine in not a causal risk factor. It is an innocent bystander’ declared  the author, Dr Bonaa.

We now know he was wrong, and why he was wrong. Smith and Refsum’s paper goes into all the detail but what has since been learnt is this:

  • B vitamins don’t lower risk if you don’t already have a high homocysteine level.
  • Anti-platelet drugs (think aspirin) and statins interfere with the beneficial action of B vitamins.
  • B12 is poorly absorbed and certain older patients with poor absorption or kidney disease are less likely to respond to oral B12 (but might get benefit from B12 injections).
  • Also lowering homocysteine with B vitamins BEFORE a person has had a stroke or a heart attack does much more effectively reduce the likelihood of them having one.

This has led to serious cardiology scientists, such as Professor David Spence, who realising the problems with a major study he had conducted, called VISP, reanalysed the results to find a clear benefit. ‘Call off the funeral’, he declared.

But, for some, sadly including the so-called National Institute of Clinical Excellence (NICE), now called the National Institute of Health and Care Excellence there will be no exhumation for homocysteine. That’s really sad because two thirds of cardiovascular deaths in the elderly happen to people with high Hcy. Not paying any attention to the actual scientific evidence due to a former misguided bias is not health, care or excellence.

Is there a Mental or Neurological Illness that Isn’t Cranked Up by High Homocysteine?

Have a look at the list of diseases below, all strongly associated with homocysteine. Take Parkinson’s for example. A recent meta-analysis shows that both homocysteine, vitamin B12, and folate status predict the onset and development of Parkinson’s.[12]

The point is that if you’re over 60 or have any concerns about any of these conditions, and especially if you already have a serious degenerative disease such as Parkinson’s, multiple sclerosis, dementia or cardio or cerebrovascular disease it is vital to check your homocysteine level and then act accordingly. If your specialist hasn’t done this they are not doing their job properly. The science is in plain sight.

Plasma Total Homocysteine as a Disease Biomarker

Insufficient B vitamin status
Folate, B12, B6, B2
Inborn errors of homocysteine and vitamin metabolism and transport
Cardiovascular diseases
Myocardial infarction
Severity of coronary artery disease
Restenosis of coronary arteries and adverse outcomes after angioplasty
Stroke mortality
Silent brain infarct
Carotid plaque area, stenosis, intima-media thickness
Intracerebral arterial stenosis
Peripheral vascular disease
Venous thrombosis
Arterial aneurysm
Arterial stiffness
Atrial fibrillation
Cerebral small vessel disease
Cerebral microbleeds
Disruption of blood-brain-barrier
Endothelial mediated dilatation – impaired
Vascular complications of diabetes
Raynaud’s syndrome
Takayasu arteritis
Thromboangiitis obliterans (Buerger’s disease)
Moyamoya disease
Behçet disease
Erectile dysfunction


Other syndromes

Metabolic syndrome
Bone disease, osteoporosis
Inflammatory bowel disease, Crohns
Non-alcoholic fatty liver disease
Renal insufficiency, chronic kidney disease
Chronic obstructive pulmonary disease
Alcohol abuse
Sickle-cell disease
Burning mouth syndrome
Atrophic glossitis
Quality of life in centenarians
Obstructive sleep apnea
Telomere shortening
Systemic lupus erythematosus (SLE)
Inflammatory response
Periodontal disease
Hearing loss
Blood lead concentration
Maternal tHcy
Pregnancy complications
Outcomes in child
– small for gestational age, fetal growth
– neural tube defects
– congenital heart disease
– orofacial clefts
– renal function
– child cognition
– child behaviour
– schizophrenia
– autism spectrum disorder
Central nervous system diseases
Incident Alzheimer’s disease/dementia
Vascular dementia, vascular cognitive impairment
Post-stroke cognitive impairment
Cognitive decline after concussion
Cognition in children
Cognition in elderly
Initiation of cognitive decline in ageing
Conversion from cognitive impairment to dementia
Cognitive decline in dementia
Atrophy of brain tissue/gray matter
Atrophy of brain white matter
White matter damage
Alzheimer brain pathology (P-tau)
Multiple sclerosis
Cognitive decline in Parkinson’s disease
Bipolar disorder
Amyotrophic lateral sclerosis/ Motor Neuron Disease
Multiple System Atrophy
Impaired motor development in infant
Early neurological deterioration after stroke
Glasgow coma scale
Autism spectrum disorder

The table lists diseases and syndromes for which there are reports of association with raised total homocysteine.Reproduced with the permission of the authors Professors David Smith and Helga Refsum from the paper Smith AD, Refsum H. Homocysteine – from disease biomarker to disease prevention. J Intern Med. 2021 Oct;290(4):826-854. doi: 10.1111/joim.13279. Epub 2021 Apr 6. PMID: 33660358.  © 2021 The Association for the Publication of the Journal of Internal Medicine 3 Journal of Internal Medicine

Testing and Lowering Homocysteine

Despite almost 29,000 studies on homocysteine getting your doctor to test your homocysteine is close to impossible. It shouldn’t be because every hospital laboratory can do this simple laboratory test. It need not be expensive.

All these studies refer to total plasma homocysteine, that is the level found not in red blood cells but in the clear serum part of blood. The issue there regarding testing has been the need to separate or spin the blood shortly after taking the sample or pass the blood through a plasma separator as some home test kits have attempted. I’ve tested home test kits and not been impressed with the correlation with serum/plasma homocysteine, which is the gold standard.

However, a breakthrough with both the fixing of blood taken using a dry blood spot, and the testing process, has occurred which now means that we at foodforthebrain.org/tests/ have an accurate and inexpensive way to test homocysteine from a dry blood spot supplied from a home test kit. This is going to be made inexpensively available all over the world, and has started with the UK and EU. The validation of this test is extremely good (with a R2 of 0.93 for those who know statistics. This also means that there will be no false positives or negatives.) Homocysteine, however, is only truly accurate if measured after fasting for 12 hours with water only being drunk. Both coffee and alcohol affect homocysteine levels, as does eating a protein-rich meal. I also advise not taking B vitamin supplements during this time or possibly for 24 hours before you test.

Fortunately Hcy is easily lowered. The simplest and most effective way to do this is with B vitamin supplements at the right dosage. Most critical is the amount of vitamin B12 they provide. The basic Dietary Reference Value that you see on supplements is 2.5mcg. Few provide more than 10mcg, which is sufficient if you don’t have raised Hcy. This will do nothing to lower a high H score. Professor’s Smith and Refsum recommend 500mcg a day – that’s two hundred times higher. This is both safe and effective especially if taken alongside B6(20mg) and methylfolate(400mcg). Also, it doesn’t take so long you bring your level down. I’ve had clients with H levels from 30 up to over 100 µmol/L bring theirs down to below 9 in under three months. In my range Connect is used for lowering homocysteine, and I’ve also included it in the new Brain Food Upgrade pack.

Other wise choices are to eat greens, beans, nuts and seeds which are high in folate; eat seafood and eggs, high in B12 and phospholipids, as well as omega-3, which methylation helps bind together to make healthy cell membranes; don’t smoke or drink in excess (one 125ml of red wine doesn’t effect homocysteine levels); don’t drink more than one coffee a day; reduce stress and insomnia and keep fit.

What Next? Upgrade your Brain AND Become a Citizen Scientist

Thanks to already well over 400,000 ‘citizen scientists we have, with the sword of digital technology, opened the oyster to uncover the true causes – all under your control – that are driving this terrible and unnecessary brain shrinkage.

Those citizen scientists have taken the time, often initially for personal interest, to discover their actual cognitive function, and completed a comprehensive questionnaire.

We hope to reach a million people around the world within a year or so making this the biggest prevention-focussed study of its kind.

Change is not going to come from the Government or the NHS. It is going to have to come from us, the people.

We ask you to take control of upgrading your brain and in the process become Citizen Scientists for better brain health for future generations.

Follow these seven steps.

STEP 1: Take the Cognitive Function Test

What you’ll learn:

  • Find out where you are on the cognitive function scale
  • Learn the most important dietary and lifestyle actions you can take
  • Take control of your mental wellbeing
  • Contribute to the Food for the Brain research process

Take the Cognitive Function Test

STEP 2: Test for the Four Keystone Biochemical Processes

A consensus of world experts concluded that lowering homocysteine with B vitamins is the easiest and most cost effective prevention action, which Oxford University’s health economists estimate would save the UK £66 million per year. However, it’s vital to test both homocysteine and Omega-3 levels, as they are co-dependent. Homocysteine-lowering B vitamins only work in those with sufficient omega-3, and omega-3 only works if homocysteine is low.

So, get tested for the four keystone biochemical processes with the DRIfT Test.

It will calculate your Dementia Risk Index functional Test (DRIfT) score. Tracking this, along with your Cognitive Function (CFT) and Dementia Risk Index (DRI) is the most comprehensive way to protect your brain.

This 4-in-1 test measures:

  • Vitamin D
  • Omega-3
  • Homocysteine
  • HbA1C

More info – Drift Test from Food for the Brain and Other Tests.

STEP 3 – Get Educated

Read my book Upgrade Your Brain – Out Now!

More info & to order – Upgrade Your Brain Book

Join me on my UK or Ireland Seminar Tour – May/June

I’m visiting 30 cities in the UK and Ireland in May/June to kick start a nationwide ‘Upgrade Your Brain’ campaign.

“We need to engage with millions of people, get nutrition education happening in schools, and most of all get heath authorities and governments around the world to take the mental health meltdown seriously and put brain health at the top of the health agenda.”

Professor Crawford says “Today’s diet bears no resemblance to the wild foods we ate during our species’ evolution to which our genome is adapted. If we don’t prioritise brain health and nutrition the continued escalation of mental ill health, starting in the 1950s, can only end in disaster.”

Dates/locations: More tour info & how to book

Sign up to my E-News

Go to the home page of this website and sign up to my E-News for more blogs/reports/videos and podcasts on brain health. Follow on Facebook (PatrickHolford) and Instagram. (PatrickHolford.UK)

STEP 4: Start a Brain Healthy Diet

The Upgrade Your Brain cooking app with brain-friendly recipes will be launching soon. It will help you make the right food choices for your brain.

Pre-order the Brain Cook App. 

STEP 5: Ensure You Get Enough of the Right Nutrients

There are three essentials for building brain cells (neurons) – omega-3 fats, B vitamins and Phospholipids. Omega-3 is bound to phospholipids by methylation which is a process that is dependent on B vitamins – B6, B12 and folate.

There are some key supplements that have been identified to support brain health. In the Holford range these are:

  • Connect: B vitamins and zinc to support healthy methylation
  • High PC Lecithin – A Rich source of 63% phospholipid
  • Omega-3 Support – 550mg of DHA and 750mg of EPA

All these are found in the Brain Food Upgrade pack

STEP 6: Spread the Word & Promote Prevention

We urge everyone to share the ‘prevention’ message with others.

You can do this by sharing social media posts and blogs/reports.

You can participate in Alzheimer’s Prevention Day on 15 May and encourage others to do the same. Take the free 3-minute online Alzheimer’s Prevention Check and get motivated to make the eight brain-friendly diet and lifestyle changes

“You are the architect of your own brain’s future health.” says neurologist Dr David Perlmutter.

Take the test for Alzheimer’s Prevention Day

Step 7: Support the ‘Prevention’ Work

‘Friends’ donate £50 a year and get so much in return. This is how we are funding our amazing research team (see foodforthebrain.org/researchteam/). We are a lean, keen, small but mighty team.

Every donation, big or small, goes right back into helping people prevent these preventable and terrible diseases such as dementia. Together, we can change the world. We need to, because time is running out. We will lose our humanity if we don’t stop this brain drain.”

All donations are put back into research, and the results of the research are shared back to people.

Give to Food for the Brain and support their work.


[1] Smith AD, Refsum H. Homocysteine – from disease biomarker to disease prevention. J Intern Med. 2021 Oct;290(4):826-854. doi: 10.1111/joim.13279. Epub 2021 Apr 6. PMID: 33660358.

[2] Pfeiffer CM, Osterloh JD, Kennedy-Stephenson J, Picciano MF, Yetley EA, Rader JI, Johnson CL. Trends in circulating concentrations of total homocysteine among US adolescents and adults: findings from the 1991-1994 and 1999-2004 National Health and Nutrition Examination Surveys. Clin Chem. 2008 May;54(5):801-13. doi: 10.1373/clinchem.2007.100214. Epub 2008 Mar 28. PMID: 18375482.

[3] Vogiatzoglou A, Refsum H, Johnston C, Smith SM, Bradley KM, de Jager C, Budge MM, Smith AD. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology. 2008 Sep 9;71(11):826-32. doi: 10.1212/01.wnl.0000325581.26991.f2. PMID: 18779510.

[4] Xu R, Huang F, Wang Y, Liu Q, Lv Y, Zhang Q. Gender- and age-related differences in homocysteine concentration: a cross-sectional study of the general population of China. Sci Rep. 2020 Oct 15;10(1):17401. doi: 10.1038/s41598-020-74596-7. PMID: 33060744; PMCID: PMC7566483.

[5] Roigé-Castellví J, Murphy M, Fernández-Ballart J, Canals J. Moderately elevated preconception fasting plasma total homocysteine is a risk factor for psychological problems in childhood. Public Health Nutr. 2019 Jun;22(9):1615-1623. doi: 10.1017/S1368980018003610. Epub 2019 Jan 14. PMID: 30636652; PMCID: PMC10261079.

[6] Li J, Feng D, He S, Wu Q, Su Z, Ye H. Meta-analysis: association of homocysteine with recurrent spontaneous abortion. Women Health. 2021 Aug;61(7):713-720. doi: 10.1080/03630242.2021.1957747. Epub 2021 Aug 1. PMID: 34334120.

[7] Dai C, Fei Y, Li J, Shi Y, Yang X. A Novel Review of Homocysteine and Pregnancy Complications. Biomed Res Int. 2021 May 6;2021:6652231. doi: 10.1155/2021/6652231. PMID: 34036101; PMCID: PMC8121575.

[8] Fan R, Zhang A, Zhong F. Association between homocysteine levels and all-cause mortality: A dose-response meta-anal- ysis of prospective Studies. Sci Rep. 2017;7:4769.

[9] Pusceddu I, Herrmann W, Kleber ME, Scharnagl H, Hoff- mann MM, Winklhofer-Roob BM, et al. Subclinical inflam- mation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study. Eur J Nutr. 2020;59:1399–411.

[10] Teng Z, Feng J, Liu R, Ji Y, Xu J, Jiang X, Chen H, Dong Y, Meng N, Xiao Y, Xie X and Lv P (2022) Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front. Aging Neurosci. 14:868777. doi: 10.3389/fnagi.2022.868777

[11] Read both 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; also 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; also  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; also 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

[12] Quan Y, Xu J, Xu Q, Guo Z, Ou R, Shang H and Wei Q (2023) Association between the risk and severity of Parkinson’s disease and plasma homocysteine, vitamin B12 and folate levels: a systematic review and meta-analysis. Front. Aging Neurosci. 15:1254824. doi: 10.3389/fnagi.2023.1254824