At the turn of the 20th century, psychiatrist Alois Alzheimer made a groundbreaking discovery by identifying the presence of clumps and tangles in the brains of individuals with dementia. These clumps, known as amyloid beta proteins, have been the leading theory behind the cause of Alzheimer’s disease. Despite numerous attempts, the development of drugs to clear these plaques has proven unsuccessful. In recent trials, the drug gantenerumab, specifically designed to eradicate amyloid beta, has failed to preserve cognitive abilities in individuals with early-stage Alzheimer’s disease compared to those given a placebo.
In two separate trials, nearly 1,000 older individuals from 30 countries received regular injections of gantenerumab or a placebo over a period of approximately two years. The level of cognitive decline was measured using the Clinical Dementia Rating scale, and the drug did indeed reduce the amount of amyloid beta in the brain as intended. However, this reduction did not result in any noticeable improvements in cognitive function. The researchers reported that “the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline.” These findings come at a critical moment for the amyloid hypothesis, as pharmaceutical companies continue to seek anti-amyloid drug approvals despite limited evidence.
The approval of drugs like aducanumab and lecanemab by the FDA has generated controversy. These drugs, like gantenerumab, use synthetic antibodies to bind to amyloid beta and facilitate its removal from the brain. However, the efficacy of these drugs in providing meaningful benefits to patients is still under scrutiny. Clinical trials with aducanumab yielded mixed results, with one trial showing promise and another failing to demonstrate any significant clinical benefit. Similarly, lecanemab showed a decrease in cognitive decline of 27% compared to a placebo group over 18 months, but the difference on the rating scale was a mere 0.45 points, potentially too minimal to impact patients’ lives positively. Moreover, concerns have been raised about adverse effects, including brain bleeds and seizures, associated with lecanemab.
With the cost of anti-amyloid drugs reaching an estimated $26,500 per year, doubts emerge about the cost-benefit ratio and whether these drugs are worth the associated risks. Lon Schneider, a professor of psychiatry, notes that the failure of gantenerumab is surprising, considering that other drugs with similar mechanisms have been granted accelerated approval by the FDA. He suggests that the duration of the gantenerumab trial might have been too short to demonstrate significant benefits for patients. Furthermore, splitting the trial into two separate studies might have diluted the potential impact. The potential for amyloid plaque reduction to have a positive effect on Alzheimer’s patients still remains uncertain.
For over a century, researchers have been investigating the role of amyloid plaques in Alzheimer’s disease. However, the development of drugs that effectively target and clear these plaques has proven elusive. In the case of gantenerumab, despite successfully reducing amyloid beta levels, there was no observable improvement in cognitive function. The approval of drugs like aducanumab and lecanemab has raised questions about the significance of their benefits and potential risks. As the search for effective treatments continues, patients and their families eagerly await breakthroughs that will offer hope in the battle against Alzheimer’s disease.