The non-essential amino acid homocysteine (Hcy) is derived from dietary protein. Its conversion to useful metabolites (S-adenosylmethionine and glutathione) requires methyl-folate and vitamins B12 and B6 as cofactors; hence Hcy blood levels rise if levels of these vitamins are suboptimal.
Patients with Alzheimer's disease (AD), vascular dementia and mild cognitive impairment (MCI) frequently have raised Hcy. This is now a recognised risk factor for cognitive decline and incident dementia.1
It reflects vitamin B depletion due to neuro-inflammatory oxidative stress, and might be an important component of the dementia process leading to neurotransmitter deficits, tau protein hyperphosphorylation and amyloid deposition.2
Case studies in cognitively impaired hyperhomocysteinaemic patients from my own general practice showed improved cognition following vitamin B and antioxidant supplementation,3 but clinical trial evidence has been equivocal for cognitively intact individuals and negative for patients with established AD.
However, long-term supplementation of folic acid, with or without vitamin B12, might benefit healthy older people with high Hcy levels.4
VITACOG is a recently completed randomised placebo-controlled two-year trial of high-dose vitamin B supplementation in elderly individuals (>70 years) with MCI.5 Treatment comprised folic acid 0.8mg, vitamin B12 0.5mg and vitamin B6 20mg. The primary outcome was brain atrophy rate measured by serial volumetric MRI scans but the trial also evaluated clinical and cognitive function.
Complete scans were available for 83 placebo and 85 treated subjects. In the treated subjects, Hcy levels fell by 22.5% but increased by 7.7% in the placebo group. Consistent with earlier reports, higher Hcy levels were associated with an increased rate of brain atrophy.
Atrophy was significantly slowed by 30% in treated individuals with a baseline Hcy level >9.5micromol/L. Those with the highest baseline Hcy (>13micromol/L) had a rate of atrophy 53% lower than the placebo group.
In the larger cohort of subjects completing the cognitive component of the trial (113 received placebo and 110 B vitamins) there was a significant benefit of B vitamins among those with Hcy >11micromol/L in scores of global cognition, and episodic and semantic memory.6
There was also an improvement in clinical rating scales (the informant questionnaire on cognitive decline in the elderly and the clinical dementia rating) in the B vitamin group, but only in subjects with Hcy >13micromol/L. Remarkably, treatment more than doubled the number of subjects with a clinical dementia rating of zero (equating to no dementia) compared with no effect in the placebo group.
In summary, the VITACOG trial shows that the combination of oral high-dose B12, folic acid and B6 significantly slows brain atrophy and cognitive decline in patients with MCI and raised Hcy. These two effects are highly dependent on baseline levels of Hcy, perhaps partly explaining discrepant results in earlier trials.
Although very welcome news, there are several practical implications and difficulties in the light of these results. Physicians and public alike are generally unaware of the association of elevated Hcy and risk of developing dementia, and even less aware of the latest evidence showing beneficial effects of Hcy reduction.
Currently, Hcy assays are neither routinely nor widely available in the UK, although they can be a useful screening test for B12 and folate deficiency. Testing for high Hcy in elderly subjects with early MCI may also have a place in determining the appropriate treatment of such patients.
If the VITACOG trial results are confirmed, patients with MCI and elevated Hcy will undoubtedly benefit from a combination of oral folic acid (0.8mg), vitamin B12 (0.5mg) and vitamin B6 (20mg). However, no such single high dose licensed formulation exists in the UK. Treatment requires a multiple item prescription increasing the cost to the patient (in England). Compliance may also be affected.
In the light of the very positive results seen in the trial it may be appropriate to consider full scale development of such a combination product.
In the meantime, my current practice with patients presenting with MCI is to measure their Hcy level and, if >10micromol/L, to treat them with folic acid 0.8mg, vitamin B6 20mg and oral vitamin B12 1mg daily; the latter is not available on NHS prescription but is available over the counter at many health stores.
I have also found additional cognitive benefit from including the antioxidant N-acetylcysteine (600mg), which further lowers Hcy by increasing its urinary excretion. While results based on individual patients are encouraging, further RCTs are required to confirm this observation.
It is of course not yet confirmed whether such intervention on a larger scale will ultimately reduce the incidence and burden of dementia. However, a recent estimate is that it has the potential to lead to a 20% reduction in risk of dementia, the financial and social implications of which are considerable.7
Another issue is how frequently should patients with MCI have Hcy levels tested? Current guidelines suggest an assessment of vitamin B status every three to five years because dietary or drug changes may lead to deficiency, the symptoms of which may be mistakenly attributed to insidious dementia and hence go undetected.
Importantly, VITACOG now sets the stage for larger and longer trials to study the effects of B vitamins on conversion rates from MCI to dementia.
The results also offer a glimmer of hope in treating a condition that has otherwise become associated with a degree of therapeutic nihilism. Physicians can now also avoid over-treatment by clearly defining those individuals who are most likely to benefit.
- Dr McCaddon is a GP in Wrexham and senior honorary research fellow at the Cardiff School of Medicine
- He is also a scientific adviser and shareholder of COBALZ Ltd, a private company developing novel B-vitamin and antioxidant supplements
1. McCaddon A. J Alzheimers Dis 2006; 9: 361-80.
2. McCaddon A, Hudson P. Future Neurol 2007; 2(5): 537-47.
3. McCaddon A. Nutr J 2006; 5: 6.
4. Malouf M, Grimley EJ, Areosa SA. Cochrane Database Syst Rev 2003: (4): CD004514.
5. Smith AD, Smith SM, de Jager C et al. PLoS One 2010; 5(9): e12244.
6. De Jager C, Oulhaj A, Jacoby R et al. Int J Geriatr Psychiatry 2011: doi: 10.1002/gps.2758.
7. Wald DS, Kasturiratne A, Simmonds M. Alzheimers Dement 2011; 7: 412-17.