from The Economist (thanks to Rick B.)
OF ALL THE medical challenges that scientists have faced, Alzheimer’s disease, the most common form of dementia, has been one of the trickiest. Between 1995 and 2021 private money spent on Alzheimer’s research came to $42.5bn, but more than 140 trials failed to yield a single drug capable of slowing the disease. Yet the tide may be turning. There are now two working drugs, offering modest benefits, on the market, and a new review paper suggests more could soon follow.
There are 182 clinical trials for Alzheimer’s treatments under way in 2025—an 11% increase on last year—testing 138 different drugs, of which 12 are likely to complete their final “phase 3” trials this year. Moreover, this pipeline includes medicines aimed at a diverse range of targets in the brain, reflecting an increasingly sophisticated understanding of the molecular processes behind Alzheimer’s and dementia.
For decades, the theory that has dominated Alzheimer’s research, and drug pipelines, has been the amyloid hypothesis. It argues that the primary cause of the disease is the accumulation of plaques of beta-amyloid proteins in the brain. These supposedly lead to a cascade of negative effects including neuronal dysfunction, brain-cell death and neuroinflammation.
The amyloid hypothesis was supported by genetic evidence, which showed mutations in certain genes within families were linked to early onset of the disease. The success of the two drugs already treating Alzheimer’s—lecanemab and donanemab, which arrived on the market in 2023 and 2024, respectively—proves that a connection exists. Both help clear amyloid from the brain, and offer modest help to a subset of patients for whom the drug is thought to be safe and useful. They slow the progression of the disease by about one-third, according to clinical trials, meaning patients can retain their quality of life for longer.
The excitement generated by these drugs has been tinged, however, with a feeling that they were not much to show for decades of effort. The singular focus on amyloid was probably misplaced. James Rowe, a professor of cognitive neurology at the University of Cambridge, says that although amyloid accumulation is a critical “early trigger” for the disease, by the time patients arrive at his clinic, other neural processes are accelerating the illness. These include the accumulation of a misshapen version of another protein, called tau; increased metabolic stress on brain cells; neuroinflammation; and degeneration of the brain’s blood supply. (continue on page 2 of www.skyline725.com)
This more nuanced understanding of Alzheimer’s is at last being reflected in drug development. That is the conclusion of Jeffrey Cummings at the University of Nevada, Las Vegas, and colleagues, in their new review, published on June 3rd in Translational Research & Clinical Interventions.
Academic experts, and investors, agree. Dame Kate Bingham is the managing partner of SV Health Investors, a venture-capital firm based in London that, in 2015, started the first fund dedicated to discovering new treatments for dementia. At the time, the drug pipeline for Alzheimer’s was mainly focused on tackling amyloid. She says the growing diversity of potential targets today gives her increased optimism.
Fully one-third of the new drugs are repurposed, which means they are already approved for use in other conditions and are being redeployed to Alzheimer’s. The appeal of this approach is that the drugs already have known safety and toxicity profiles, and can be approved quickly and developed cheaply. One of the better known is semaglutide, a diabetes and weight-loss drug whose anti-inflammatory and metabolic benefits have led to its being tested as a treatment for mild cognitive impairment. The drug piromelatine, meanwhile, works on melatonin and serotonin receptors in the brain, which help regulate sleep. As healthy sleep is thought to increase the rate at which amyloid and other waste proteins are cleared, improving it may slow the progression of Alzheimer’s.
Then there is AR1001 (also known as mirodenafil), which was originally developed for erectile dysfunction and is being tested for its neuroprotective properties. The drug increases levels of a molecule in the brain called cGMP which, in turn, activates pathways that support the survival of nerve cells and improve connections between them. Drugs of this kind are known to improve blood flow, so AR1001 might also improve the brain’s vascular health.
Another repurposed drug is nabilone, which interacts with the cannabinoid receptors in the body. (The most well known molecule of this kind is tetrahydrocannabinol, the active compound in cannabis). It was originally developed to treat nausea and vomiting in those undergoing cancer chemotherapy. It is now being tested as a potential treatment for agitation and behavioural problems in those with Alzheimer’s. Guanfacine, a drug that improves attention and executive function in those with ADHD, is also being tested to see if it can offer similar benefits.
Repurposed drugs do not necessarily have a higher chance of success in late-stage trials than those with a novel mechanism. Indeed, Dame Kate argues that innovative approaches which use new molecular targets, rather than repurposing, will have the greatest impact on the disease.
Fresh approaches
One area of innovation is centred on drugs that can tackle inflammation in the brain. Particular attention is being paid to brain cells called microglia, which play an important role in the brain’s immune response and, most probably, its fight against Alzheimer’s. Microglia have been described as acting as the brain’s fire service, police and binmen, because they simultaneously respond to emergencies, maintain order and clear up debris. A number of drugs are trying to target the protein TREM2 on the surface of microglia in the hope of boosting their activity.
Combinations of drugs are also being tested. For example, it is hoped that pairing dasatinib, a cancer drug, with quercetin, a molecule derived from plants, will clear ageing and dysfunctional cells. Drug combinations that target different pathways and components of an illness have made big inroads into other complex diseases such as cancer and HIV.
Some of the errors of the past have been corrected. Dr Rowe says that early attempts to design amyloid-clearing drugs did not remove enough amyloid, or did so too slowly. The patient selection in trials was also poor, with many patients included who—it later turned out—did not have Alzheimer’s at all.
Today’s trials still have blind spots, warns Antonella Santuccione-Chadha, the founder of the Women’s Brain Foundation, a non-profit based in Switzerland that studies how sex affects brain and mental health. Many still fail to differentiate patients by sex, she says. Yet women are twice as likely to develop Alzheimer’s, a difference that cannot be explained solely by their longer lifespans, and the disease seems to progress differently in their brains. At any given stage of the disease, tau proteins spread farther in women than in men, says Dr Chadha.
It would help the trials—and patients—if more people were tested for Alzheimer’s earlier on, so that they could be enrolled to try the new drugs. A single register of those with the disease would also be useful, making it easier for patients to find trials, and for drug companies to find patients.
Much, therefore, remains to be done. But for those suffering from a horrible and as yet insurmountable disease that steals so many minds, there is also some much needed hope. ■
Great to read this.