The Alzheimer’s tau platform trial: a trial of amyloid-targeted therapies and its potential for a daily oral pill
There are trials of combinations of approaches with amyloid-targeting therapies. The Alzheimer’s tau platform (ATP) trial, for example, will test multiple tau-targeted therapies both alone and combined with an anti-amyloid drug. The -secretase modulator is being combined with lecanemab.
Multiple labs found that lysosomes become enlarged and damaged before plaques appear in Alzheimer’s disease. So do endosomes, another part of cells’ waste-clearance apparatus. The idea is that this disposal failure causes waste — including amyloid-β — to accumulate inside cells, ultimately killing them and spilling ready-made plaques into the brain. Rubinsztein says that removing anirritant may be what is going on in the trials. “But the primary cause of cell death is lysosomal dysfunction, not amyloid-β.”
A group led by Ralph Nixon, a neurobiologist at New York University who pioneered this theory, has found evidence of bulging neurons with swollen lysosomes spilling waste into the brain in both mice and brain tissue from people with Alzheimer’s disease. The crux of this dysfunction seems to be impaired regulation of lysosomes’ pH, leaving them insufficiently acidic to degrade molecules.
As well as amyloid-β plaques, Alzheimer’s is also characterized by tangles of the protein tau that accumulate inside neurons. Most people think that amyloid-β pathology triggers the development of tau tangles, but that does not necessarily mean that clearing away amyloid-β will put the brakes on tau as well. At some point, there might be a point when the pathology develops and becomes self-sustaining. “You can remove amyloid, but you won’t stop that process,” says De Strooper.
There were problems with experimental -secretase modulators but it is doing well in early-stage trials. “They didn’t see any mechanistic side effects, and the toxicity seems to be overcome,” says De Strooper. This approach could make a daily oral pill a reality. In the future, the -secretase modulators will be the most important therapy for Alzheimer’s disease.
Another focus is to target the disease process even earlier, and prevent the build-up of amyloid-β plaques in the first place. Amyloid-β is a fragment of a larger protein called amyloid precursor protein (APP) that crosses cell membranes. APP is slice in two places by the two enzymes that created it. Lowering the number of plaques is achieved by smallmolecules that stop the formation of plaques.
If a vaccine were developed, it would probably be used to prevent familial Alzheimer’s in people who carry mutations that cause early-onset disease. People with mutations such as APOE4, which increase the risk of the more common sporadic form of the disease, might also be candidates.
An early attempt to make this work was abandoned in 2002 after some trial participants developed inflammation of the brain and the membranes that surround it. But now, armed with an understanding of why this happened (part of the vaccine provoked a response by a type of white blood cell called a T cell) and how to avoid it, researchers are returning to the concept. It is not ready for prime time but there are attempts to design vaccination studies, says Selkoe.
Rather than deliver ready-made antibodies, one line of work is to prompt the body to produce its own, using an amyloid-β vaccine. This would be straightforward to administer and cheaper than antibody infusions. Selkoe says that you need something simple and safe in order to get a large amount of people who don’t normally go to medical school.
The development of pathology using biomarkers in the blood could be used to identify people who would benefit from preventive treatment, if the drugs prove more effective when administered before symptoms develop.
There are sometimes serious side effects of the drugs. Reducing these will be key to shifting the risk–benefit equation in the drugs’ favour. In the pivotal trial of lecanemab1, 21.5% of people treated developed brain swelling or bleeding, collectively known as amyloid-related imaging abnormalities (ARIA). This is usually asymptomatic, but around one-quarter of people with ARIA experience confusion, headaches or dizziness. Seizures and even death are rare but not uncommon.
Lecanemab and donanemab were approved by the FDA in the same year. Both are slow in cognitive decline. Whether this is clinically meaningful has been hotly debated; some clinicians argue that individuals will not notice a difference, but others say that even a moderate slow down delivers real benefit to a person with the disease and their family. Charlotte Teunissen, who is a neuroscientist at Amsterdam University Medical Center, said a 30% less-steep decline does mean something. Even six months longer in a coherent state, she says, “is the difference between being able to have meaningful conversations with your children about their lives, or not”.
It might be difficult to understand just how tough a diagnosis of Alzheimer’s disease can be for an individual and their family until you have experienced it personally. Around seven million new Alzheimer’s cases are diagnosed every year and so many of us will feel sorry for ourselves.
Another major breakthrough of the past five years is the development of blood tests that can distinguish Alzheimer’s from other forms of dementia. Although such diagnostics look set to be crucial tools for physicians and researchers, there are already concerns over their potential misuse.
The understanding of Alzheimer’s is growing and could lead to new ways of preventing and treating the disease. A woman from ruralColombia with a rare collection of genetic defects inspired a line of attack. And growing evidence suggests that pathogens might play a part in the development and progression of Alzheimer’s. The mechanisms that cause disease progression between genders could lead to better care for all, as researchers try to understand them. This work is being threatened by some funding cuts ordered by the administration of President Donald Trump. The fight against Alzheimers disease is not safe in the US.
We would like to take this time to acknowledge Eli Lilly & Company’s financial support of the Outlook. As always, Nature retains sole responsibility for all editorial content.