A Cure for Alzheimer’s?

There is nothing romantic about Alzheimer’s disease, a condition as different as could be from the spes phthisica, the heightened creativity and sensitivity said to be caused by tuberculosis. The only similarities are that in the days when the spes was being celebrated by La Traviata and La Bohème, tuberculosis was as common – and incurable – as Alzheimer’s is today. It was no surprise, then, that massive media interest was generated earlier this year when the pharmaceutical company Eli Lilly announced that its monoclonal antibody donanemab slowed cognitive decline by 35 per cent in some Alzheimer’s sufferers.

Trial results published last November showed that another monoclonal antibody, lecanemab, made by Biogen and Eisai, also slowed cognitive decline, by 27 per cent over 18 months. Both drugs target amyloid beta, a protein that builds up outside brain cells in patients with Alzheimer’s. That they have some beneficial effect is good news, though tempered by serious side effects – seizures and bleeding into the brain, fatal in a few – and expense: a year of treatment with lecanemab costs $26,000.

‘Each time history repeats itself, the price goes up.’ A low-cost therapy was introduced a century ago that often stopped the progress of a common dementia in its tracks. A significant minority of people who had had untreated syphilis for a couple of decades developed a lethal condition known as general paralysis of the insane. A common initial manifestation was hyperbolic exaltation: the patient might claim to have hundreds of wives and thousands of children (it was much commoner in men); hand bystanders cheques for millions written on dirty bits of newspaper; and talk incessantly save when he was writing and write incessantly save when he was talking. Fits then started, the dementia became deeper and deeper, and after about five years he died, paralysed and bed-ridden.

The Viennese psychiatrist Julius Wagner-Jauregg observed that some psychotic patients had improved after developing a fever. In 1917 he infected nine GPI patients using blood from a malarial soldier. Four showed improvement and two were cured. More trials were done, with similar results. By the early 1920s malaria treatment of GPI was being used worldwide. Wagner-Jauregg won a Nobel Prize in 1927. In the UK, patients were infected with malaria using mosquitoes bred and infected at Horton Hospital, Epsom. Ten thousand people were treated. Its laboratory became a WHO reference centre.

Despite quinine, the occasional patient was killed by therapeutic malaria. Anti-amyloid monoclonals have also been associated with a few fatalities. It isn’t possible to predict how long they will continue to be the best that can be done for Alzheimer’s; their benefits are still not as good as malaria treatment was for GPI. Much targeted research on Alzheimer’s continues.

Penicillin has made GPI a clinical rarity. A single shot kills the causative Treponema bacterium stone dead, and its genome is so specialised that it can’t develop resistance. But when Alexander Fleming discovered penicillin he wasn’t looking for a cure for syphilis: his only connection with the disease had been the money he made treating private patients for it with the arsenical drug 606 (which doesn’t work in GPI). His research was on bacterial pigmentation, an unimportant topic then and now. And chance played enormous roles in the discovery.

A cool spell was necessary for the Penicillium mould to grow and produce penicillin on the famous plate, which had not been put in an incubator but forgotten when Fleming was on his summer holidays at his six-bedroom Georgian house near Newmarket (probably bought using proceeds from his 606 private practice). Directly below Fleming’s laboratory a fungus specialist was growing a menagerie of moulds to investigate their roles in causing asthma: the Penicillium spores probably didn’t come through the windows of Fleming’s laboratory, which were seldom if ever opened, but almost certainly drifted up from downstairs. And the Penicillium discovered by Fleming by accident turned out to be a much better penicillin producer than most other strains.

Fleming had the devil’s own luck. The links between Alzheimer’s disease and amyloid have been under investigation for more than twenty years. The scientific consensus is that it is not the only molecule involved. On the balance of probabilities, identifying the full house will need some Fleming moments. And it may well be that such success won’t come from targeted research on the disease but from work on an unrelated subject, as with the discovery of penicillin.