Alzheimer's DiseaseIntroduction
Dose-response relationship



The articles by Dewson et al in the February and March editions of GM1 are a welcome survey of some of the evidence concerning dietary supplements and prevention of Alzheimer’s disease. I would like to bring out some key principles underlying nutritional interventions to help the clinician judge the validity of the claims and counter-claims in the literature. I will illustrate my comments by reference to the possible role of lowering plasma homocysteine by B vitamins in modifying Alzheimer’s disease progression.

Two particular principles are relevant: first, the dose-response relationship and, second, interactions between individual micronutrients and between micronutrients and genetic polymorphisms.


Dose-response relationship

For any micronutrient there is a dose-response relationship between the tissue (usually blood) concentration or intake of the nutrient and the biological response (Figure 1)

Nutrient intake / concentration graph

Figure 1 - A cardinal principle of nutrition. The curves show the typical relationship between a nutrient and biological outcome(s) that are influenced by the nutrient. Higher concentrations of the nutrient may be required for some outcomes (parallel shift, red versus blue), or the slope of the relationship may change according to interaction with genetic or environmental factors (yellow). Much higher concentrations of the nutrient may lead to toxic effects (dashed line).3

As an example of a parallel shift in the curve relating response to concentration we can consider vitamin B12. The blue curve might represent the situation when the response being assessed is the prevention of macrocytosis, while for the prevention of brain atrophy and of cognitive decline higher concentrations are needed, as shown by the red curve. This means that we should not automatically extrapolate from the nutrient requirements for one outcome to those for another different outcome. For vitamin B12 this is particularly important because many of the outcomes that relate to the nervous system appear to require considerably higher concentrations/intakes of the vitamin than do the haematological markers.2

In considering the results of clinical trials of a dietary supplement, we must always ask: what is the baseline status of the nutrient in question? If the baseline nutrient concentration is within the plateau region of the dose-response curve for the particular outcome, then we cannot expect any change in the response upon treatment. If we do not know the dose doseresponse curve for a complex outcome, such as slowing cognitive impairment, we can simply ask whether the placebo group showed any change over time. If there was no cognitive decline in the placebo group, then it is likely that the concentration of the nutrient is in the plateau range and so we cannot expect administration of a nutritional supplement to slow cognitive decline.

Several published trials and meta-analyses display this weakness, as we have reviewed.3 The VITACOG trial illustrates this principle. In this trial, older people with mild cognitive impairment were recruited from the Oxford community and were given either a placebo tablet or a tablet containing high doses of 3 B vitamins (0.8mg folic acid; 0.5mg vitamin B12; 20mg vitamin B6) that are known to lower plasma homocysteine concentrations. The trial was designed to see if lowering homocysteine would slow the accelerated rate of whole brain atrophy over two years. The homocysteine level was 30% lower in the active treatment group and the mean rate of brain atrophy was 27% slower. But the effect of B vitamin treatment depended upon the baseline homocysteine: only those participants with homocysteine above the median (11μmol/L) showed slowing of the atrophy rate. The higher the homocysteine, the greater the effect such that for those in the top quartile (>13μmol/L) the rate of atrophy was slowed by 53%.4 This result nicely illustrates the principle embodied in the dose-response curve since high homocysteine reflects poorer B vitamin status (but no-one was clinically deficient).

Exactly the same result was obtained for the slowing of cognitive decline: only those participants with homocysteine above the median showed a beneficial effect of B vitamin treatment: in these subjects the treatment markedly slowed memory decline. In participants with homocysteine in the top quartile, there was even a significant clinical improvement, as revealed by the Clinical Dementia Rating (CDR) score.5 But in those with homocysteine below the median there was no cognitive or clinical benefit of B vitamins, presumably because their B vitamin status was already adequate.

In a further analysis, we looked at the effect of B vitamin treatment on the atrophy of specific brain regions and found a highly selective slowing of atrophy in those particular regions that are known to be affected in Alzheimer’s disease. The slowing of atrophy in these regions was again limited to subjects with baseline homocysteine above the median but, for these subjects, the atrophy of the specific regions was slowed by almost 9-fold.6

Using a Bayesian network method we were able to show the following causal chain of events: B vitamins (mainly B12) lower homocysteine, which slows the rate of regional brain atrophy, which in turn slows cognitive decline. These results are consistent with the view that B vitamins, by lowering homocysteine, can modify the disease process in mild cognitive impairment and thus, probably, in Alzheimer’s disease. If that is the case, a screening programme for raised homocysteine in memory clinics would detect many patients who could benefit from B vitamin treatment. Such a policy has been adopted in Swedish memory clinics, but not yet in the UK. Considerable cost savings would follow from adopting such a policy in the UK.7



The second important principle of nutritional intervention is that nutrients interact. We consume a balanced diet and not a mixture of individual nutrients. Dietary patterns have been found to be important in preventive medicine and so we might expect to find evidence of beneficial interactions between individual nutrients in relation to prevention of dementia. The VITACOG trial illustrates this principle. We found that the beneficial effect of B vitamins on slowing of brain atrophy and slowing of cognitive decline was dependent upon the omega-3 fatty acid status of the participants: only those with a good omega-3 status responded.8,9 Likewise, we found that the slowing of brain atrophy rate by omega-3 fatty acids was dependent upon a good B vitamins status, only occurring in those with low homocysteine. These results could partly explain why several B vitamin trials have failed and, likewise, could explain why results of omega-3 trials, as pointed out by Dawson et al1 are contradictory. Another kind of interaction is between nutrients and genetic polymorphisms. Two examples are that vitamin B12 status in a population is only related to cognition in those who carry the ε4 allele of the gene for ApoE10 and, likewise, the beneficial effect of omega-3 fatty acids on cognition seems to be limited to those with the ε4 allele.11



To conclude, I am confident that the use of dietary supplements is a valid approach to prevention of Alzheimer’s disease, but we need to bear the above principles in mind when reading the literature and when selecting our patients.


David Smith Department of Pharmacology, University of Oxford

Conflict of interest: none declared.



1. Dawson D, O’Kelly A, Richards G. Can dietary supplements prevent or slow the progression of Alzheimer’s disease? GM Journal 2017; 47: 33–60, accessible here:

2. Smith AD, Refsum H. Do we need to reconsider the desirable blood level of vitamin B12? J Intern Med 2012; 271(2): 179–82 3. Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 2016; 36: 211–39

3. Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 2016; 36: 211–39

4. Smith AD, Smith SM, de Jager CA, et al. Homocysteinelowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment. A randomized controlled trial. PLoS ONE 2010; 5(9): e12244.

5. de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry 2012; 27(6): 592–600

6. Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 2013; 110(23): 9523–8

7. Tsiachristas A, Smith AD. B-vitamins are potentially a costeffective population health strategy to tackle dementia: Too good to be true? Alzheimers Dement (NY) 2016; 2: 156–61

8. Jernerén F, Elshorbagy AK, Oulhaj A, et al. Brain atrophy in cognitively impaired elderly: the importance of long-chain omega-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr 2015; 102(7): 215–21

9. Oulhaj A, Jernerén F, Refsum H, et al. Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in Mild Cognitive Impairment J Alzheimer’s Dis 2016; 50(2): 547–57

10. Vogiatzoglou A, Smith AD, Nurk E, et al. Cognitive function in an elderly population: Interaction between vitamin B12 status, depression, and apolipoprotein E E4: The Hordaland Homocysteine Study. Psychosom Med 2013; 75(1): 20–29

11. Yassine HN, Braskie MN, et al. Association of docosahexaenoic acid supplementation with Alzheimer Disease stage in apolipoprotein E epsilon4 carriers: a review. JAMA Neurol 2017; 74(3): 339–47