Failure of yet another anti-amyloid drug is hailed as ‘the beginning of the end for Alzheimer’s’, according to the Times headline today. It certainly was the end for two, possibly three volunteers given the experimental drug, according to the BBC [1] .

Like other anti-amyloid drugs, the level of significant adverse effects was unacceptably high. According to the Eli Lilly’s press release [2] (no trial has been published) one quarter (24%) of those on the drug developed brain swelling and 24% brain bleeding. It is these adverse effects that can cause death. I’m not quite sure how the BBC conclude only ‘1.6% developed dangerous brain swelling’. Perhaps they meant the level of swelling that could be fatal? But brain swelling and bleeding is not a good idea in elderly people with pre-dementia. Apart from anything else this means they’d need frequent and expensive brain scans to check whether or not this was occurring with each monthly treatment.

The press release inflated the apparent benefit in the usual way saying ‘29% less reduction, compared to placebo’ on the main measure of Clinical Dementia Rating , thus showing the relative, not absolute effect on cognitive assessment. What it actually means is that those on the placebo degenerated from a clinical perspective and those on the drug degenerated a bit less so.

The measure in question, Clinical Dementia Rating (Sum of Boxes), is a questionnaire, administered by a health professional who asks the patient’s partner or carer to rate their memory and 6 aspects of their general functional ability as being normal, questionable, mild, moderate or severe. Depending on the carer’s assessment each question adds either zero (if normal), 0.5, 1, 2 or 3 to the ‘Sum of Boxes’ score, which can therefore range from zero (nothing wrong) to 18 (severe impairment in everything). This is balanced by an interview with the participant who answers questions related to each of the domains/aspects of functional ability, and the doctor or rater scores the CDR taking both the subjective and objective evidence into account. The previous anti-amyloid drug trial, which reported less than half a point (0.45) difference, has been criticised for potential ‘unblinding’. This means that the carer or partner, when asked about how they thought the ‘patient’ was doing, might be biased to provide a more optimistic assessment because they knew they were on the drug from the adverse effects and thus hoped there was some improvement.

So, what happened in this trial? Those on the placebo got 2.4 points worse over 18 months and those on the drug treatment got 1.7 points worse. That’s relatively 29% less worse, but the absolute improvement is the difference, namely 0.49 points, similar to the previous ant-amyloid treatment reporting 0.45 points. So, no meaningful difference between the previous failed drug, nor the one before it which reported 0.39 points on an 18-point scale. According to a British Medical Journal editorial “minimum changes of 0.98 in mild cognitive impairment and 1.63 in mild Alzheimer’s disease are meaningful.” [3] This means that these results were clinically meaningless. All data from the drug company’s own press release.

How this hails the ‘beginning of the end’ of Alzheimer’s beggar’s belief. When compared with the effect of B vitamins or omega-3 fish oil in similar randomised controlled placebo trials [4], these results pale into insignificance, and especially the combination of the two[5]. In those with high homocysteine, given B vitamins, and with sufficient omega-3, there was 73% less brain shrinkage [6] and a third ended the trial with an overall Clinical Dementia Rating of zero [7] – i.e. no longer diagnostically labeled as having dementia. In other words, not less worse, but actually better. Why does this not get reported?

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Reference & Links

¹ https://www.bbc.co.uk/news/health-65471914

²  https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional

³  Walsh S, Merrick R, Richard E, Nurock S, Brayne C. Lecanemab for Alzheimer’s disease. BMJ. 2022 Dec 19;379:o3010. doi: 10.1136/bmj.o3010. PMID: 36535691.

⁴  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; see also 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

⁵  Oulhaj, A et al, ‘homocysteine as a predictor of cognitive decline in Alzheimer’s Disease’, Int J Geriatric psychiatry, 25(1): 82-90 (2010)

⁶  Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 2013; 110: 9523-8.

⁷ 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.

Responding to the ‘feverish media coverage heralding a new era of disease modifying treatments’, described by the BBC as a ‘momentous breakthrough’ a scathing editorial in the British Medical Journal says: “Hyperbolic rhetoric gives patients and their families false hope, which clinicians must address, and pre-empts regulatory decision making.”

“Such treatment has been long hoped for,” they say. “However, the null effects on cognition of other anti-amyloid agents, the tiny effect on cognition reported for [the new drug] lecanemab and concerns about safety mean that perspective is needed.”

“The prevailing narrative is that this trial “succeeded” where others have “failed.” In reality, lecanemab, like other anti-amyloid agents, successfully cleared amyloid from the brain. This clearance had no discernible effect on cognition in some trials, a very small and non- significant effect in other trials, and a very small significant effect in the latest trial. The overall trial evidence tells us that successful amyloid clearance in adults with early Alzheimer’s disease has either no effect or a tiny effect on cognitive decline.” 

“Previous attempts to quantify the minimum clinically important difference in the trial’s primary outcome measure—the Clinical Dementia Rating (CDR) sum of boxes score (range 0-18 —suggested that minimum changes of 0.98 in mild cognitive impairment and 1.63 in mild Alzheimer’s disease are meaningful. After 18 months of treatment with lecanemab, differences of 0.35 and 0.62 for those with mild cognitive impairment and mild Alzheimer’s disease, respectively, fell well short, representing only around a third of what a minimum clinically important difference might look like.”

Both B vitamins and omega-3 have achieved a clinically significant reduction in the CDR by these criteria, as well as improving other measures of cognition, and in reducing the rate of brain shrinkage. The rate of brain shrinkage reduction of this kind of drug is 2% compared to up to 73% less shrinkage with B vitamins in those with sufficient omega-3. Yet both UK, US and EU government and medical agencies have repeatedly declined funding a definitive trial of both B vitamins and omega-3.

The BMJ editorial expresses serious concerns about safety of this class of drug, which is really an antibody injection. “As with other anti-amyloid agents, lecanemab comes with substantial safety concerns. During the trial, 12.6% of participants treated with lecanemab developed brain oedema (swelling), 22% of whom were symptomatic.  A further 17.3% experienced brain haemorrhage; and 6.9% experienced adverse events severe enough to discontinue the trial.” That means that 30% of drug trial participants had a serious adverse effect.

While the number of deaths in the main trial were comparable between the drug and placebo group “more information is needed about two deaths reported during the trial’s open label extension. Both participants had brain haemorrhage, possibly associated with taking lecanemab alongside anticoagulants or thrombolysis.”

They say that “Lecanemab if licensed is likely to cost tens of thousands of pounds a year for each patient. In addition, health systems would need to provide PET scans or lumbar puncture to determine eligibility, fortnightly infusions of the drug indefinitely, and repeated MRI [scans] to monitor for adverse events, all of which is far beyond the capacity of most countries, even those with well-resourced healthcare systems.” B vitamins and omega-3 have no side-effects, other than knock-on health improvements, and cost pennies, not thousands of pounds.

Pressure for approval and clinical use, the BMJ says, is likely to be fierce. “Viewed objectively, however, lecanemab is not the hoped for “game changer.” Rather, it is further evidence that anti-amyloid therapies do not produce clinically meaningful benefits for people with Alzheimer’s disease. Weighed against the scale and severity of adverse events and substantial practical barriers to widespread use, lecanemab is unlikely to represent a favourable risk-benefit balance for patients or value for money for health systems.”

The fully referenced BMJ editorial can be viewed here.

If you are concerned about age-related cognitive decline, dementia or Alzheimer’s please take our free, validated Cognitive Function Test here and sign up to join our COGNITION programme, to help dementia-proof your diet and lifestyle. Also, please support our work in helping teach people who to prevent dementia by becoming a FRIEND of Food for the Brain here.

Today, the US FDA has licenced aducanumab, an amyloid protein drug developed for dementia treatment. It has already failed in clinical trials, adding to the 300 studies that have failed. In a normal world, if you test a theory 300 times and it fails 300 times you discard the theory – that amyloid plaques in the brain are what causes Alzheimer’s.

While aducanumab has been demonstrated to reduce brain amyloid, it hasn’t been shown to deliver any meaningful improvement in cognition. A recent meta-analysis of 14 anti-amyloid drug trials found no significant slowing of cognitive decline despite lowering of amyloid. Nor has it been shown to reduce the rate of brain shrinkage.

In contrast, the combination of B vitamins and sufficient omega-3 has been shown to reduce brain shrinkage by 68% over the period of one year in research by Professor David Smith and colleagues at Oxford University. No drugs have shown such a positive effect on brain shrinkage. What’s more, memory loss was not observed to decline further and 70% of participants were classified with a Clinical Dementia Rating of zero.

In many cases dementia may be preventable – not with drugs but with nutrition and lifestyle changes.

Omega-3 and B vitamins are a Dynamic Duo

B vitamins and omega-3 are so important for mental health because the membrane through which brain signals are passed is made out of an omega-3 fat called DHA, which attaches to a phospholipid. DHA is 98% of the structural fat of the brain. Seafood is a rich source of DHA and phospholipids, and phospholipids can also be found in eggs.

These two vital components of brain cells are actively bound together by a process called methylation. Methylation is dependent on B vitamins, especially B12, folate and B6. Zinc also has a vital role to play. If these nutrients are low a toxic amino acid called homocysteine starts to accumulate in the blood stream. More often than not the critical deficiency is vitamin B12, found in fish, eggs, milk and meat. The ‘deficiency’ may be due to dietary deficiency, but also may be due to malabsorption triggered by a lack of stomach acid, potentially exacerbated by certain drugs.

Putting Prevention into Action

Scientific research shows that the following factors are key in the prevention of dementia:

·     Sufficient intake and absorption of B vitamins
·     Sufficient intake of omega-3
·     Sufficient intake of antioxidants including Vitamin C
·     A low sugar diet
·     Good digestion
·     Having an active mind and social life
·     Regular physical activity
·     Good sleep and reducing stress

These are all areas in which you can make simple changes to support your brain health. Take our popular Cognitive Function Test today to discover the actions you can take that will make the biggest difference. We encourage everyone over 40 to take this test.

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Food for the Brain is crowdfunding to support the upgrade of its Cognitive Function Test, already taken by 360,000 people around the world.

COG-NITION® is a personalised and interactive ‘brain upgrade’ programme designed to help people make positive changes step by step, with the support of an engaging and encouraging community. It has been created in collaboration with leading dementia experts including Professors David Smith and Jin-Tai Yu.

By supporting our crowdfunding campaign, you can help us launch COG-NITION® this autumn. The ultimate goal is to save a third of people from getting dementia, which means a 100,000 fewer cases a year in the UK alone.

As a charitable foundation, we rely on donations to continue our vital work in this area. Please give whatever you can – every £1 you give helps someone somewhere make the changes to prevent dementia.

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