Alzheimer’s: Why prevention is better than drugs – but less profitable
By Patrick Holford
After 40 failed trials for drugs injecting anti-amyloid antibodies (AAAs) one, Lecanemab[i], has finally shown a modest benefit on cognitive function in those with early-stage Alzheimer’s. But they come with a terrible cost – adverse effects that include brain swelling and haemorrage which occurred in one in five trial participants.. When a similar drug, Aducanumab, was conditionally approved by the US FDA last year, despite nine out of ten of their experts voting against it, many resigned in protest[ii]. Yet the pressure on pharma to get an amyloid drug to market, having spent over $42 billion[iii], is immense.
Let’s consider the alternative
Prevention with simple, doable changes to diet, lifestyle and supplementation with B vitamins and omega-3 fish oils.
The two most relevant measures of success of any treatment are reduction in the rate of brain shrinkage and a reduction in clinical dementia symptoms which lead to a diagnosis.
In relation to brain shrinkage the best AAAs have achieved is 2% less brain shrinkage. In a landmark trial by Professor David Smith and colleagues at the University of Oxford, B vitamin supplements, given to those with pre-dementia (mild cognitive impairment) have achieved a reduction in the rate of brain shrinkage of 52%, up to 73% in those with sufficient omega-3.[i] This effect was shown in those with raised blood levels of homocysteine, a marker for B vitamin status that is raised in approximately half of pre-dementia patients and many more with Alzheimer’s. We now know that B vitamins need omega-3 to make the biggest difference, and vice versa.[ii]
Figure 1. Reduction in brain shrinkage B vitamins and omega 3 vs AAAs. Sources: Jernerén F, Elshorbagy AK, Oulhaj A, et al. Am J Clin Nutr. 2015 Jul;102(1):215-21; Schwarz AJ, Sundell KL, Charil A, et al. Alzheimers Dement (N Y). 2019 Jul 30;5:328-337; Smith AD, Smith SM, de Jager CA, et al. PLoS One. 2010;5(9):e12244.
Clinical Dementia Rating (CDR) with B vitamins and Omega 3’s
What about actual clinical improvement, called Clinical Dementia Rating (CDR), which is what counts for the person concerned? A CDR score of zero means no clinically significant cognitive impairment. In the Oxford trial on B vitamins 65% of participants on B vitamins with higher omega-DHA status ended the 2 year trial with a clinical dementia rating of zero compared with 25% receiving placebo.[i] It was more than twice as effective as the recent drug. In a Swedish omega-3 trial those with sufficient B vitamin status, also had a marked reduction in clinical dementia rating, which was reduced by 1.5 points compared with placebo after 6 month’s treatment with omega-3.[ii] The improvement in clinical dementia rating reported for Lecanemab, which was a modest 0.45 point reduction. This was marginally better than a 0.39 difference for Aducanumab, compared to placebo.[iii] [iv] In other words, no AAA drug has even reduced a CDR score by 1 point but both B vitamins and omega-3 have.
Figure 2. Comparison of Clinical Dementia Rating (CDR) reduction between synergistic B vitamin/Omega-3 supplementation and two AAA drugs. Sources: Oulhaj A, Jernerén F, Refsum H, et al. J Alzheimers Dis. 2016;50(2):547-57; Eisai press release; Tampi RR, Forester BP, Agronin M. Drugs Context. 2021 Oct 4;10:2021-7-3; Jernerén F, Cederholm T, Refsum H, et al. J Alzheimers Dis. 2019;69(1):189-197.
A trial in Holland, called B-proof, which had shown no significant effects overall in those supplementing B vitamins, recently reported that those with higher Omega-3 levels had a significant improvement in cognitive function. A French[i] and Chinese study[ii] reported a similar finding – the combination of B vitamins and omega-3 shows clear improvements in cognitive function – better than achieved by AAA drugs, without adverse effects.
So, on all three counts – brain shrinkage, cognitive function and clinical dementia rating – B vitamins plus omega-3 – wins out at a fraction of the cost since nutrients cannot be patented which is the requirement for the scale of profitability required by pharma.
Blood Sugar Levels and their impact
But, there’s two other points to make. Firstly, B vitamin and omega-3 status are but two of eight known actions that reduce risk or improve these critical criteria. Others are sugar, antioxidant rich fruit and veg, vitamin D, exercise, cognitive stimulation, gut health, sleep and stress.[i] Having a high blood sugar level from age 35 predicts Alzheimer’s risk.[ii] Being diabetic or having high insulin levels, which is a consequence of eating too many refined sugar and carbs, doubles risk.[iii] Having a high carb intake is associated with increasing amyloid plaques in the brain – so why not tackle the upstream cause? One study reported that “Those who ate the healthiest diet had an 88% decreased risk of developing dementia and a 92% decreased risk of developing Alzheimer’s disease.”[iv] Increasing lean muscle mass with resistance exercise is associated with better cognitive function and brain volume.[v] The charity foodforthebrain.org have a free, validated online Cognitive Function Test, followed by a Dementia Risk Index questionnaire, that not only measures your cognitive function, but also shows you exactly what your risk is and how to reduce it by targeting your ‘weakest links’ in these eight known prevention steps.
Then, there’s the issue of side-effects. For each of these prevention steps there are none. Or rather, there are plenty – less risk for diabetes, heart disease, arthritis, premature ageing, better energy, sleep and weight control to name a few.
For the AAA drugs the side-effects are potentially devasting. Since one in five can be expected to experience brain swelling and microbleeds, regular brain scans will be necessary to monitor for these frequent complications. Is it right to expose an older person with cognitive decline to this scale of risk and medical intervention for such a modest benefit? The annual cost of treatment is expected to be above $10,000 but that doesn’t include the cost of medical monitoring or the cost of treatment when things go wrong. The cost benefit equation just doesn’t add up.
Early Intervention
Writing in the Financial Times last year Professor Smith says “ Your editorial is correct in saying ‘A resurrection of the amyloid approach must not divert resources and attention away from other ways to tackle dementia, which are in earlier stages of research and might give better results.’ These alternative approaches include identifying and then treating modifiable risk factors for dementia, of which about a dozen are already known. These account for about half of the cases of Alzheimer’s disease .” The high price proposed for the drug is disturbing, especially when a very much cheaper alternative treatment is available: high-doses of B vitamins and omega-3 from seafood or supplements. He estimates that early intervention , targeting all the prevention steps recommended by the Food for the Brain Foundation could cut a person’s risk by two thirds.
For more details on Alzheimer’s prevention visit: https://foodforthebrain.org/preventing-alzheimers-disease/
Alzheimer’s Is Preventable – LEARN more now
WE currently have 2 events on sale so that you can take a deep dive on this topic:
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References:
[1] Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. J Alzheimers Dis. 2016;50(2):547-57. doi: 10.3233/JAD-150777. PMID: 26757190; PMCID: PMC4927899.
[2] Jernerén F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Freund-Levi Y. Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study. J Alzheimers Dis. 2019;69(1):189-197. doi: 10.3233/JAD-181148. PMID: 30958356.
[3] Cummings JL, Goldman DP, Simmons-Stern NR, Ponton E. The costs of developing treatments for Alzheimer’s disease: A retrospective exploration. Alzheimers Dement. 2022 Mar;18(3):469-477. doi: 10.1002/alz.12450. Epub 2021 Sep 28. PMID: 34581499; PMCID: PMC8940715.
[6] Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. J Alzheimers Dis. 2016;50(2):547-57. doi: 10.3233/JAD-150777. PMID: 26757190; PMCID: PMC4927899.
[7] Jernerén F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Freund-Levi Y. Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study. J Alzheimers Dis. 2019;69(1):189-197. doi: 10.3233/JAD-181148. PMID: 30958356.
[9] Awaiting actual Lecanemab, trial – see press release ref 1 above
[10] Maltais M, de Souto Barreto P, Bowman GL, Smith AD, Cantet C, Andrieu S, Rolland Y. Omega-3 Supplementation for the Prevention of Cognitive Decline in Older Adults: Does It Depend on Homocysteine Levels? J Nutr Health Aging. 2022;26(6):615-620. doi: 10.1007/s12603-022-1809-5. PMID: 35718871.
[11] Li M, Li W, Gao Y, Chen Y, Bai D, Weng J, Du Y, Ma F, Wang X, Liu H, Huang G. Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial. Eur J Nutr. 2021 Jun;60(4):1795-1808. doi: 10.1007/s00394-020-02373-3. Epub 2020 Aug 28. PMID: 32856190.
[13] Zhang X, Tong T, Chang A, Ang TFA, Tao Q, Auerbach S, Devine S, Qiu WQ, Mez J, Massaro J, Lunetta KL, Au R, Farrer LA. Midlife lipid and glucose levels are associated with Alzheimer’s disease. Alzheimers Dement. 2022 Mar 23. doi: 10.1002/alz.12641. Epub ahead of print. PMID: 35319157.
[15] Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M. Midlife healthy-diet index and late-life dementia and Alzheimer’s disease. Dement Geriatr Cogn Dis Extra. 2011 Jan;1(1):103-12. doi: 10.1159/000327518. Epub 2011 Apr 27. PMID: 22163237; PMCID: PMC3199886.