The full approval of the new Alzheimer’s drug, lecanemab, marketed as Leqembi, by the FDA (Food and Drug Administration) this month is likely to boost sales, even at the cost of $26,500 per person per year (plus the costs of brain scans and physician monitoring) despite its benefits and safety risks continuing to be a source of debate.

Medicare, the major provider of care for the over 65s in America, has said it will only fund patients whose doctors take part in a nationwide registry that gathers real-life data to study the usefulness of these drugs – a move opposed by the Alzheimer's Association. The clinical trials’ data showed that Leqembi slowed the progress of the disease by around five months although it did not improve brain function (cognition). Experts are concerned about the risks: 20 percent of participants experienced brain swelling and bleeds, known as Amyloid-related imaging abnormalities (ARIA), with three reported deaths. Professor Jason Karlawish, who was a site co-investigator on clinical trials sponsored by Biogen, Eisai and Lilly, is calling for a Risk Evaluation and Mitigation Strategy. Professor Robert Howard, Professor of Old Age Psychiatry, UCL Division of Psychiatry, UCL, said, ‘I’m afraid I would not want to give this to one of my patients or to a member of my family who had Alzheimer’s disease.’

Professor Howard added, ‘The benefits of lecanemab are so modest as to be undetectable in an individual treated patient. Although 27% slowing of disease course sounds impressive, this is not strictly what the analysis of the trial data showed. It’s important the results are discussed honestly, accurately and without spin.'

Professor Karlawish is professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine and co-director of the Penn Memory Center (REMS). He writes, ‘The measures of the benefits of a treatment for Alzheimer’s disease are difficult to translate into practice. The benefit of cancer treatments such as CART-T is measured with a simple language: patients live longer. That’s easy to measure and to understand.

‘In dementia treatment, survival has never been measured as a benefit. Instead, we speak of living longer in a certain state of mind. The measures we use — cognition and day-to-day function — and the significance of changes in them aren’t readily understandable. The primary endpoint of the lecanemab trial, the Clinical Dementia Rating-Sum of Boxes (CDR-SB), isn’t used in clinical practice. Most patients and clinicians haven’t a clue what it is. Measures of caregiver outcomes such as burden are similarly opaque.’

‘Patients on both donanemab and lecanemab have died.’ (Donanemab is a drug that works in a similar way to lecanemab. Manufacturer Eli Lilly is yet to send its data to the FDA.)

Some Alzheimer’s scientists who have long argued that amyloid isn’t the whole answer feel that Leqembi’s middling performance only confirms their thesis.’The most likely consequence of this medication is to take resources and attention away from addressing basic supports for older adults with cognitive impairment’ said Maria Glymour, chair of the Department of Epidemiology at the Boston University School of Public Health. ‘The money spent on expensive drugs like lecanemab [Leqembi] would be better invested in fighting diseases like high blood pressure and diabetes, which hasten dementia, and on community-based services for older adults.’

There is also frustration that there were only 20 Black participants in the drug’s trials. Carey Gleason, a clinical neuropsychologist at the University of Wisconsin School of Medicine and Public Health said that many Black volunteers in the trial “screened out,” because PET scans showed relatively low levels of amyloid in their brains. Leqembi works by removing amyloid, so the trial organizers excluded patients — regardless of their Alzheimer’s symptoms — if their PET scans were negative, although Blacks are up to twice as likely as whites to have Alzheimer’s.

The lower amyloid load highlights the controversy surrounding the basic premise of the amyloid/tau hypothesis. A third of the general population aged 70 and over have amyloid deposits, increasing to more than half of over 90 year olds, yet do not develop Alzheimer’s.

In its review of the costs and benefits of lecanemab, a 15-member panel appointed by the Institute for Clinical and Economic Review gave the drug low marks, saying, ‘A majority of the California Technology Assessment Forum was clearly unconvinced that the current evidence adequately demonstrates that lecanemab provides a net benefit to patients.’

A stock market website says that ‘the major risk in holding Biogen [stock] with respect to Leqembi is that surprisingly few physicians [will] prescribe it due to its ARIA side effect profile and/or because many patients refuse the complex testing required to confirm the necessary diagnosis to receive a prescription. Another risk is that ARIA side effects occur more frequently in the real-world setting and that this information, which should be widely available through the patient registry, dissuades physicians from writing Leqembi prescriptions.’

Meanwhile, research continues down different avenues. Scientists at the University of Pittsburgh School of Medicine found that the build-up of amyloid protein in the brain may in itself not be enough to cause symptoms. They discovered that immune cells called astrocytes were activated in patients who developed Alzheimer’s. ‘This puts astrocytes at the centre as key regulators of disease progression, challenging the notion that amyloid is enough to trigger Alzheimer’s disease,’ said Dr Tharick Pascoal, senior author of the study and associate professor of psychiatry and neurology at the university.

A study published in Frontiers in Immunology found that inhaling menthol enhanced cognition in mice and reduced the concentration of interleukin-1-beta (IL-1b), a protein pivotal to the inflammatory response. Previous studies have also shown a link between diminished olfactory senses and the onset of Alzheimer’s disease symptoms.

An anti-amyloid vaccine has been developed by Swiss firm AC Immune to provoke an immune response, or immunogenicity, in adults with Down syndrome. Researchers believe the new vaccine is potentially a safer and more effective alternative to treatments such as lecanemab. “The reason we are using Down syndrome individuals is that they have very defined genetics," said Professor Andrea Pfeifer, CEO of AC Immune. "Basically since birth they have beta-amyloid, which leads to plaques in Alzheimer’s disease. By the time they are 20, they develop Alzheimer’s like symptoms. By the time they are 40, they all have such symptoms. At the age of 60, the probability is almost 100% that they will have Alzheimer’s disease."

The data obtained through Medicare’s Registry will give insight into the efficacy and the side effects of Leqembi, and it is encouraging to know that many different approaches are being explored. Hopefully, real solutions will be found that will help families like TV presenter Fiona Phillips, diagnosed with Alzheimer’s last year, who revealed that her parents, grandparents and an uncle had lived with it. Meantime, we follow the NHS’s health advice on the best way of preventing it.