The process of memory decline and brain shrinkage associated with Alzheimer’s Disease is thought to occur over a 30 to 40 year period, hence the need for screening from age 50. Both high homocysteine (Hcy) levels, and low folic and B12 levels in blood correlate with increasing risk for AD. This article reviews the research evidence that support this position and discusses the follow on research questions: at what point in the process is cognitive decline reversible; and what dose of nutrients confers protection?
Alzheimer’s Disease (AD) is characterised by a progressive loss of cognitive functions including memory, language, judgment, praxis and orientation and is diagnosed on the basis of shrinking in the thickness of the medial temporal lobe, which is considered to be the primary pathology that generates the associated symptoms.  The detectable, preclinical phase of AD presents as mild cognitive impairment (MCI). Episodic memory impairment is the most common initial symptom of MCI. Poor performance in verbal or visuospatial memory recall, processing speed, attention and executive function tasks requiring planning or judgement & semantic fluency are common predictors of Alzheimer’s risk. These are included in Food for the Brain’s Cognitive Function Test, which has been validated against existing best tests for these functions .
The process of memory decline and brain shrinkage associated with AD is thought to occur over a 30 to 40 year period, hence identifying the need for screening from age 50.
Figure 1 below shows the spread of Alzheimer’s neurodegeneration over 50 years.
Figure 1: Spread of Alzheimer’s neuro-degeneration over 50 years (used with permission of AD Smith, adapted from PNAS, 2002 paper)
High homocysteine, and low folic acid and B12 status as markers
Both high homocysteine (Hcy) levels, and low folic and B12 levels in blood correlate with increasing risk for AD according to a systematic review. Another review, in 2008, concludes that: ‘Of seventy-seven cross-sectional studies on more than 34,000 subjects and 33 prospective studies on more than 12,000 subjects have shown associations between cognitive deficit or dementia and homocysteine and/or B vitamins’.
Hcy levels also predict and correlate with rate of cognitive decline, as does B12 status. There is, therefore, ample evidence to propose that lowering homocysteine by giving appropriate supplemental levels of homocysteine lowering nutrients, including B6, B12 and folic acid, would reduce risk. The main research questions are then: at what point in the process is cognitive decline reversible; and what dose of nutrients confers protection?
Homocysteine-lowering B vitamin treatment
Does lowering Hcy by supplementing B vitamins arrest cognitive decline?
Four studies have been published in this regard.
- In older adults (>50 years) with raised Hcy (>13mmol/l), but not diagnosed with MCI, supplementing folic acid (0.8mg/d) versus placebo for three years resulted in a highly significant improvement in the memory, information processing speed and sensorimotor speed group than in the placebo group.
- Professor David Smith and his group at the Optima Project at the University of Oxford, investigated the effects of giving B vitamins versus placebo in a Randomised Control Trial (RCT), to those with MCI, measuring brain shrinkage with an MRI scan, as well as cognitive function. In this study the level of Hcy, above 9.5 mmol/l, correlated with accelerated brain shrinkage and cognitive decline. Those given folic acid (0.8mg/d), vitamin B12 (0.5 mg/d) and B6 (20mg/d) had a significant reduction in the rate of brain shrinkage as shown in Figure 2 below.
Figure 2: Brain scan images showing a reduction in the rate of brain shrinkage in the active treatment group (used with permission of AD Smith, PLos ONE 2010)
The rate of atrophy in participants with homocysteine >13 mmol/L was 53% lower in the active treatment group as shown in Figure 3 below.
Figure 3: The active treatment group showed a 53% lower atrophy rate (used with permission of AD Smith, PLos ONE 2010)
A greater rate of atrophy was associated with a lower final cognitive test scores. Also, the cortical regions of the brain that were relatively protected by the B vitamins are similar to those described as declining in those who develop AD.
- Dr Celeste de Jager, part of the Optima Project, evaluated changes in cognition in those with MCI in the previous study, either given B vitamins or placebo. The B vitamins slowed cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine.
A further study headed by Professor David Smith found those people with raised homocysteine given B vitamins, compared to placebos, had an eight-fold reduction in shrinkage of the medial temporal lobe, which is the specific area of the brain that shrinks in Alzheimer’s.
Figure 4: The active treatment group with raised baseline homocysteine showed more than an eight-fold reduction in Alzheimer's related areas of the brain (used with permission from G.Douaud, PNAS. Yellow denotes area of significant atrophy in 2 years)
- Dr Paul Aisen and colleagues at the University of California, gave homocysteine-lowering B vitamins to those already diagnosed as suffering from mild to moderate Alzheimer’s. Patients were not selected on the basis of Hcy values (average Hcy was 9.1mmol/l at baseline), and brain scans were not conducted. The patients received folic acid (5mg/d), B12 (1mg/d), and B6 (25mg/d) over a period of 18 months. No overall difference occurred in the rate of cognitive decline in those on the supplements versus placebo. However, when the patients were divided into those with high and low cognitive test scores at the start, those who had milder Alzheimer’s did significantly respond; those taking the B vitamins only slightly worsened over 15 months, while those on the placebo showed a steady decline. The average drop in homocysteine over the 18 months was from 9.1 to 6.8µmol/l.
- Dr Kwok at the Chinese University in Hong Kong gave homocysteine lowering B vitamins (folic acid 5mg, B12 1mg) to those with mild to moderate AD or vascular dementia and reported no further decline of cognitive function, but only in those with raised homocysteine (>13µmol/l).
- Dr Jerneren at Oxford University analysed the data from the previous Smith study  showing 53% less overall brain shrinkage in those starting with high homocysteine given B vitamins, but dividing the subjects into high, medium and low omega-3 plasma levels. Those with low omega-3 status at the start of the trial showed no effect from the B vitamin treatment while those in the highest tertile for omega-3 showed ~70% decrease in rate of brain shrinkage, bring their level of brain shrinkage down to that seen in healthy elderly who do not develop dementia. 
These studies suggest that homocysteine-lowering B vitamins can, at least, arrest cognitive decline and possibly improve it in people over age 50, with or without cognitive decline, but with a raised Hcy level (>9.5 mmol/l), and may arrest cognitive decline in those with mild AD, but not in moderate to severe AD. However, it is conceivable that AD patients with raised Hcy may respond differently.
Further research is needed to determine if these improvements prevent the development of AD, and also to further elucidate what combination and intake of homocysteine lowering nutrients have the most significant clinical effect.
Is homocysteine a marker or a cause of brain damage?
An article in Nature Reviews/Neurology(2011) confirms the growing evidence supporting raised homocysteine levels as a likely primary predictor and potential cause of the brain damage that identifies AD. A further review in 2011 elucidates the various hypotheses and evidence for homocysteine being key in the causation of AD-related brain damage . These include homocysteine and its derivatives as neurotoxins, damaging DNA and the neurons that are the hallmark of AD. Homocysteine is also an indicator of disrupted methylation, which leads to raised levels of amyloid and t'au proteins that are central to the formation of neuritic plaques and neurofibrilliary tangles found in the Alzheimer's brain. Raised homocysteine leads to increased oxidative stress and damage to the blood-brain barrier. It also impairs circulation by increasing cerebrovascular damage. The evidence for homocysteine and disrupted methylation being causal to the neurodegeneration seen in AD is further strengthened by the recent clinical trial evidence  showing homocysteine-lowering B vitamin treatment markedly reducing shrinkage in the medial temporal lobe.
For some years a small number of GPs have been implementing a B Vitamin based homocysteine (Hcy) management approach and reported good outcomes.
"Patients presenting with mild cognitive impairment frequently have raised blood homocysteine levels; I routinely measure this in all such cases. There is now good evidence for lowering elevated levels with high dose B-vitamins. I also prescribe the antioxidant NAC to further lower homocysteine. In my experience, I have found significant clinical improvement from this approach." Dr Andrew McCaddon, GP in Wrexham
- Smith, A.D, ‘Imaging the progression of Alzheimer pathology through the brain’, PNAS, 99(7):4135-7 (2002)
- (Morris JC. Mild cognitive impairment and preclinical Alzheimer’s disease. Geriatrics 2005; (Suppl): 9–14.; Winblad B, Palmer K, Kivipelto M et al. Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004; 256: 240–6.)
- Peterson. Mild cognitive impairment: prevalence, prognosis, aetiology, and treatment. J Int Med 2004; 256: 183–94.)
- De Jager CA, Hogervorst E, Combrinck M, Budge MM. Sensitivity and specificity of neuropsychological tests for mild cognitive impairment, vascular cognitive impairment and Alzheimer’s disease. Psychol Med 2003; 33: 1039–50.; Perry RJ, Hodges JR. Attention and executive deficits in Alzheimer’s disease. A critical review. Brain 1999; 122(Pt 3): 383–404.); Oulhaj A. et al., ‘Predicting the time of conversion to MCI in the elderly’ Neurology® 2009;73:1436–1442
- Van Dam, F. and van Gool, W.A., ‘Hyperhomocysteinemia and Alzheimer’s disease: A systematic review’, Archives of Gerentology and Geratrics, 48: 425-430 (2009)
- Smith A.D., ‘The worldwide challenge of the dementias: a role for B vitamins
and homocysteine?’, Food Nutr Bull, 29(2 Suppl): S143–72 (2008).
- Oulhaj, A et al, ‘homocysteine as a predictor of cognitive decline in Alzheimer’s Disease’, Int J Geriatric psychiatry, 25(1): 82-90 (2010)
- Smith A.D. and Refsum H.,‘Vitamin B-12 and cognition in the elderly’, Am J Clin Nutr, 89(2):707S–11S (2009): Tangney C. et al., ‘Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline’, Neurology, 72(4):361–7
- Durga, J et al, ‘The effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomized, double blind, controlled trial’, Lancet, 369(1):208-212 (2007)
- Smith, A.D. et al., ‘Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial’, Public Library of Science ONE, 5(9) (2010)
- Douaud G et al., ‘Disease-modification in MCI with homocysteine-lowering B vitamins slows atrophy of particular brain regions: the Vitacog trial.’ The Journal of Nutrition, Health & Aging, Volume 15, Supplement 1, 2011
- De Jager, C. et al., ‘Cognitive and clinical outcomes of homocysteine lowering B vitamin treatment in mild cognitive impairment: a randomized controlled trial’, Int J Geriatr Psychiatry (2011)
- Douaud, G., et al. (2013) Preventing Alzheimer's disease-related gray matter atrophy by B vitamin treatment. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9523-8
- Aisen P. et al., ‘High-dose B vitamin supplementation and cognitive decline in Alzheimer disease’, JAMA, 300(15):1774–83 (2008).
- Kwok, T., et al. (2011) A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clinical Nutrition, 30: 297-302.
- Sachdev,P.S. Nat.Rev.Neurol.7, 9-10
- Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD (2015). Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 2015 Jul;102(1):215-21
- Zhuo, J. M., H. Wang and D. Pratico. Is hyperhomocysteinemia an Alzheimer's disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci (2011) 32: 562-571.
- Trustram-Eve, C., de Jager C. A. (2013) Piloting and validation of a novel self-administered online cognitive screening tool in normal older persons: the Cognitive Function Test. Int J Geriatr Psychiatry. 2013 Jun 11. doi: 10.1002/gps.3993