Neuro Athletes,

I’m coming to you LIVE from San Francisco! This is my first time here and I have to say, it is really beautiful. I went on a very short sightseeing tour this morning and ran some hills! In my last email I mentioned my advisory role with Tonal which is why I am here. Although I have not had that much time to sightsee, I am happy that I was able to see the most important things this morning!

After my morning run I sat with one of the performance directors and he asked me about the biomarkers for Alzheimer’s Disease (AD). I’m guessing he asked me this because my talk was primarily focused on resistance training for brain health across the lifespan. We could go on for a week discussing the biomarkers of AD but let’s touch on one marker that I’m sure you have never paid attention to.

When we hear the word “Dementia” and “Alzheimer’s Disease” we immediately think of the APOE genes but there is one amino acid that we should get our attention and that is homocysteine.

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Primer

Homocysteine is a sulfur amino acid that does not occur in the diet, but it is an essential intermediate in normal mammalian metabolism of methionine. Hyperhomocysteinemia results from dietary intakes of Met, folate, and vitamin B12 and lifestyle or from the deficiency of specific enzymes, leading to tissue accumulation of this amino acid and/or its metabolites. Severe hyperhomocysteinemic patients can present neurological symptoms and structural brain abnormalities, of which the pathogenesis is poorly understood.

Homocysteine

Homocysteine (HCY) is an amino acid, present in blood. Vitamins B12, B6 and folate break down homocysteine to create other chemicals your body needs. High homocysteine levels may mean you have a vitamin deficiency. Without treatment, elevated homocysteine increases your risks for dementia, heart disease and stroke.

Specially, HCY is a sulfur amino acid that does not occur in the diet, but it is an essential intermediate in normal mammalian metabolism of methionine. Hyperhomocysteinemia (when HCY levels are elevated) results from dietary intakes of Met, folate, and vitamin B12 and lifestyle or from the deficiency of specific enzymes, leading to tissue accumulation of this amino acid and/or its metabolites. When levels are too high this hardens the smooth muscles of arteries, reducing flexibility. There is also increased risk of blood clots, or venous thrombosis.

What Does Homocysteine Do?

When it interacts with the B vitamins, homocysteine converts to two substances:

• Methionine, an essential amino acid and antioxidant that synthesizes (creates) proteins.

• Cysteine, a nonessential amino acid synthesized from methionine that reduces inflammation, increases communication between immune cells and increases liver health.

HCY & the Brain

When it comes to HCY and the brain, there are a few things to consider:

1. High HCY levels can lead to neurodegenerative diseases such as AD

2. High HCY levels are associated with ischemic stroke

3. Hyperhomocysteinemia and rain atrophy

Alzheimer’s Disease: A number of recent studies have addressed the issue of Hcy as a possible risk factor for AD. The two major proposed mechanisms for neuronal damage in AD are the accumulation of amyloid β-peptide (Aβ) and the abnormal phosphorylation of tau. One study examined the relationship of the plasma total homocysteine level measured at base line and measured eight years earlier to the risk of newly diagnosed dementia on follow-up. They found that the risk of AD increased by 40% for every 5 μmol/L rise in HCY levels.

Ischemic Stroke (IS):

When is comes to IS those with the lowest HCY were those least likely to die from stroke. The study which was published in the journal Stroke in 2015, measured levels of HCY in a total of 3,799 patients admitted to hospital for acute ischemic stroke. They were monitored for over 48 months, and those who at the beginning of the study had the highest HCY levels were those most likely to die from stroke during the follow-up period.

Brain Atrophy: The relationship between HCY and brain atrophy (where parts of the brain start to shrink) has been examined in a number of cross sectional studies. One study found that elevated HCY was a significant risk factor [OR=2.3 (CI: 1.03–5.09)] for high ‘anterior ventricle–brain ratio’ (span of lateral ventricles to brain), a measure of central atrophy, and this was not explainable on the basis of increase white matter lesions.

This study also found that higher HCY was independently related to smaller hippocampal widths on MRI.

Homocysteine as a Neurotoxin

The adverse effects of folate deficiency and elevated Hcy levels on the developing brain have been well documented. One study found that HCY has now been implicated in increased oxidative stress, DNA damage, the triggering of apoptosis and excitotoxicity, all important mechanisms in neurodegeneration. The brain may be particularly vulnerable to high levels of HCY in the blood because it lacks two major metabolic pathways for its elimination: betaine remethylation and transsulfuration.

HCY Reference Ranges

There is no consensus about the upper reference limits for plasma homocysteine concentrations. The ‘normal’ range for healthy individuals is considered to be between 5 and 15 µmol/L. However, levels as low as 6.3 µmol/L are thought to confer an increased risk. Each 5 µmol/L can increase the risk of coronary heart disease events by approximately 20%.

The good news is that homocysteine levels can be tested. High levels can, in many cases, be normalised through diet and vitamin supplementation. The most important nutrients that help lower homocysteine levels are folate, the vitamins B12, B6 and B2, zinc and trimethylglycine (TMG).

What causes high HCY?

Let’s start with diet. The level of circulating HCY is determined by the amount of B vitamins in food (B12, folate, and B6).

Around 1 in 200,000 people have a rare genetic disease called homocystinuria, where a defective enzyme means that HCY accumulates in blood.

More commonly, some people have a genetic variant called MTHFR, which if inherited from both parents can mean they cannot metabolise HCY properly, resulting in elevated levels.

• We all have MTHFR, but there are variants of the gene

• The two common polymorphisms (gene variants in the MTHFR gene) are so spread out in the population that what you actually see as a gradient of MTHFR activity that’s fairly even spread across the population.

Certain conditions can also lead to hyperhomocysteinemia. The major route of clearance of HCY from blood is the kidney, and chronic kidney disease patients commonly have raised HCY and higher incidence of vascular complications.

What This Means for You

There is mounting clinical and experimental evidence that suggests that HCY acts as a neurotoxin and therefore is a risk factor for brain atrophy and neurodegenerative diseases.

High homocysteine levels usually indicate a deficiency in vitamin B-12 or folate.

A normal level of homocysteine in the blood is less than 15 micromoles per liter (mcmol/L) of blood. Higher levels of homocysteine are split into three main categories:

• Moderate: 15-30 mcmol/L

• Intermediate: 30-100 mcmol/L

• Severe: greater than 100 mcmol/L

You can get your HCY checked with a standard blood tests, just ask your provider about this when you go next time.

While it’s possible to lower high homocysteine levels, there’s not enough research to determine whether treatment can prevent associated diseases.

If diagnosed with hyperhomocysteinemia, discuss your treatment options with your doctor. Proper treatment and some lifestyle changes can help to ensure a higher quality of life.

Until next time…

Louisa x

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