Homocysteine, Cognition, and B-Vitamins

Homocysteine, Cognition, and B-Vitamins

My memory is not as good as it used to be, which is something I should be taking more seriously than I do, since research has indicated that “older people with mild cognitive impairment (MCI) are at risk of dementia and have a higher brain atrophy rate”.

It has also been established that elevated homocysteine levels are associated with MCI, brain atrophy, and dementia. In this newsletter, we are going to take a look at exactly what that means, and what we can do about it.


Briefly, homocysteine is a chemical in the body (technically an amino acid), which like many of our chemicals is required at low doses for proper functioning, but in excess can lead to states of disease.

In a healthy state, three of the B-vitamins break down homocysteine into other chemical compounds we require. However, if we are deficient in these three B’s (B6, B12, folate), homocysteine levels rise, causing damage to the lining of arteries, and the potential for excessive blood clotting, which can increase the risk of blockages in the blood vessels.

Both these mechanisms increase our risk for heart disease and stroke, but, more germane to our subject, elevated homocysteine is also associated with an increased risk for MCI, brain atrophy, and dementia.

Seems simple enough: just ensure you are getting sufficient amounts of these three B-vitamins, since studies confirm that, in most cases, supplementing with these vitamins can reduce serum homocysteine. (Though these studies also indicate that vitamin B12 and folate are more important for homocysteine reduction than vitamin B6 is.)

However, when we look at studies that attempted to use B vitamins to improve cognitive function in older people (with or without MCI or Alzheimer’s disease), results were inconsistent. Researchers wondered why that might be, and set out to see if there was a reason for this inconsistency.

Clinical Trials

They started by looking at the VITACOG trial from the UK. This study was designed to determine the effect of VITAmins on COGnition, and hoped to discover if using B vitamins (B6, B12, and folic acid) to lower homocysteine, might improve cognition in patients with MCI. And it did.

“In this trial, there was a significant reduction of whole brain atrophy rate over 24 months with B vitamins. At the same time, there was a modest improvement in executive function. In the subgroup with high homocysteine (≤13 μmol/L) at baseline, B-vitamin treatment led to slowing of decline in episodic memory, semantic memory, Mini-Mental State Examination and Clinical Dementia Rating (CDR) and a marked reduction in atrophy rate of key brain regions like the medial temporal lobe.”

The other study examined in this analysis was done in Hong Kong (HK), and differed from the UK study by using a lower dose of folic acid (400 mcg), and not including B6 in their regimen. This study showed no benefit of B vitamins on cognitive function. However, the most important finding of the HK study was that “aspirin was found to have a significant negative interaction effect on B vitamins in cognitive functioning”.

As well, in the UK, VITACOG trial, “aspirin use was also incidentally found to have a borderline significant negative interaction with B vitamins in slowing whole brain atrophy rate”.

Given the similarity of the two trials, and the fact they both used the same CDR scale to determine outcome, our researchers pooled the data sets from the two trials in order to examine the effects of these B vitamins on cognitive functioning in older people with MCI. Specifically, they sought to more closely examine “the potential interaction effects of aspirin in cognitive functioning and brain atrophy”.

As mentioned above, there were some differences in the two studies. Whereas the HK study used only 400 mcg of folic acid and no B6, the VITACOG study used 800 mcg of folic acid and 20 mg of B6. (Both studies used 500 mcg of B12 in the cyanocobalamin form.)

Furthermore, the UK subjects had a higher rate of aspirin use, stroke, and smoking, than the HK subjects, and overall the VITACOG subjects had a significantly higher rate of whole brain atrophy than those in the HK trial.

Nonetheless, “both B-vitamin formulations lowered serum homocysteine by about one-third, and previous trials did not suggest significant additive effects of vitamin B6 in combination with vitamin B12 and folic acid, in either the extent of homocysteine-lowering or cognitive outcomes”. And, the combined data of both studies showed a significant reduction in brain atrophy from the use of B vitamins.

All of which confirmed pre-existing data linking high homocysteine levels to the development of Alzheimer’s disease (AD). So it was no surprise that other cognitive malfunctions would also show a relationship to homocysteine.


Now, let’s look at what the researchers considered to be the most important finding of this pooled data analysis: “the negative interaction effect of aspirin on the cognitive effect of B vitamins”. And this negative interaction effect was significant for cognitive functioning in subjects with MCI, independent of comorbidities (e.g., stroke, diabetes).

The conclusion of their research was very clear: “it is noteworthy that B vitamins slowed brain atrophy very significantly in aspirin non-users, but not significantly so in aspirin-users”.

Now, of the three B vitamins used, it was determined that it was the folic acid which was the one most likely to have interacted negatively with aspirin. They determined this because B6 was not used in the HK trial, and other studies in which older subjects only received vitamin B12 never found any evidence of interaction with aspirin.

These scientists believe that aspirin may have antifolate effects, which is further confirmed by other research. Namely: “oral administration of 650 mg aspirin every 4 hours for three days induced a significant but reversible fall in total and bound serum folate and a small rise in urinary folate excretion; aspirin in vitro also displaced significant amounts of bound serum folate in a dose related manner; when using aspirin (5–8 g daily) to treat inflammation, Baggott et al. noticed an inhibition of folate-dependent dihydrofolate reductase (DHFR) enzyme.”

However, the authors did point out that it is unclear if low-dose aspirin has similar antifolate effect.

Folic Acid

Folic acid is a synthetic form of folate, natural folate being found in a variety of plant foods (especially dark, leafy greens), but also in liver and seafood. It is required to produce healthy red blood cells, and a deficiency can lead to cancer, heart disease, and as established above, to dementia and other cognitive disorders.

Because folic acid is not folate per se, it requires that the body convert folic acid into folate, by using “dihydrofolate reductase” (DHFR). “It is possible that aspirin may inhibit the upregulation of DHFR in the liver, which normally occurs with folic acid supplementation, resulting in higher concentrations of circulating unmetabolized folic acid (UMFA).”

It is hypothesized that high levels of circulating unmetabolized folic acid may impede the transport of active folate into the brain, resulting in cerebral folate deficiency, and leading to cognitive impairment.

More Evidence Against Aspirin

So, it has become clear that there is a major drawback to using aspirin at high doses on a regular basis. But what danger is there to those who use low-dose aspirin regularly, for its antiplatelet action, believed to help prevent myocardial and stroke?

Well, unfortunately other studies have also suggested a negative interaction between aspirin and folic acid in stroke prevention. Analysis of “the HOPE-2 trial suggested a larger benefit of B-vitamin therapy for stroke prevention among those not receiving antiplatelet drugs (mainly aspirin), and analysis of the VITATOPS trial found that B vitamins prevented further strokes in stroke patients only in those not taking aspirin”.

And, the few studies that did show benefit to supplementing with folic acid for stroke prevention, “involved subjects with low or no usage of aspirin”.

Why does this occur? The authors speculate that folic acid may impair the antiplatelet and anti-inflammatory effects of aspirin.

Let’s take a closer look at that mechanism.

“The anti-platelet effects of aspirin are due to its inhibition of prostaglandin synthesis by inhibiting cyclooxygenase (COX)-1 and COX-2 enzymes. Both COX-1 and COX-2 activities have been implicated in AD (Alzheimer’s disease) pathology. Biological mechanisms include inhibition of neuroinflammatory responses, reduction in amyloid-β formation and tau phosphorylation.”

Furthermore, population studies have consistently shown that aspirin users are less likely to have AD than nonusers. “Although a large trial of low-dose aspirin in older people did not find lower incidence of dementia over 5 years (56), it remains possible that aspirin may slow cognitive decline in older people with MCI. This was borne out in our analysis in that among placebo group subjects in both trials of older people with MCI, aspirin users had significantly less cognitive decline than aspirin non-users. It is therefore possible that folate interferes with the neuroprotective effect of aspirin in older people with MCI.” (Study)

Folic Acid vs Folate

But is it folate, or folic acid supplements that interfere with this potential neuroprotective effect of aspirin? (Also remember that synthetic folic acid is added to enriched flour, so one wishing to avoid it will also have to avoid white flour products.)

Now might be the time to address methylation. As I have discussed elsewhere, that 30 to 40% of the population who have methylation issues (either over or under methylators), are unable to convert folic acid into usable folate. For that fairly large group (large enough to skew study results), the only form of folic acid they should ingest, outside of food, is methylfolate.

Unfortunately, it will be sometime before the scientific community redoes all these studies with the superior form of folic acid, which would help us determine if this is indeed the problem.

Fortunately, NutriStart isn’t waiting, and thanks in part to some encouragement by our customers, last year we replaced our folic acid in the NutriPods B-complex with methylfolate (also known as 5-methyltetrahydrofolate, 5-MTHF, or L-5-MTHF).


“After excluding aspirin users, this study showed convincing evidence that B vitamins either improved or prevented deterioration in global cognitive functioning as well as reducing rates of brain atrophy in older people with MCI. Whether B vitamins can prevent or delay onset of dementia in this high-risk group requires a larger and longer trial.”

NutriPods for Men
NutriPods for Women

Sign Up For Our Newsletter

* indicates required
  • Contact

  • NutriStart Vitamin Company

  • 14-755 Vanalman Avenue

  • Victoria, BC

  • 1-800-813-4233

Scroll to Top