The treatment of Alzheimer’s
Secretase modulators in Alzheimer’s disease: How much do you need to start worrying about the development of amyloid- plaques?
Mutations in three genes that can cause familial Alzheimer’s disease are known to affect APP processing, and result in the production of more or longer strings of amyloid-β. These longer proteins are more prone to clumping in plaques than are shorter forms, leading some researchers to think that tipping the balance in favour of short lengths of amyloid-β could be of benefit. The ratio of long to short needs to be shifted because of the long forms catalyse aggregation.
Llysosomes are enlarged and fail before Alzheimer’s disease plaques appear. 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. “Maybe what’s going on in the trials is you’re removing an irritant, which has a small effect,” says Rubinsztein. lysosomal dysfunction is the main cause of cell death.
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. Insufficient regulation of lysosomes’ pH may be the crux of the problem.
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 a certain point, the pathology might self-sustaining, and continue to develop regardless. De Strooper says that you can remove amyloid, but it won’t stop the process.
There have been issues with experimental -secretase modulators, but they are showing promise in early-stage trials. “They didn’t see any mechanistic side effects, and the toxicity seems to be overcome,” says De Strooper. If this approach proves effective, it could make a cheap, daily oral pill possible. According to Selkoe, the -secretasis modulators will become one of the major causes of 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. amyloid- is created by two enzymes that slice APP in two places. Small molecules to target these enzymes could stop plaques from forming.
If a vaccine were developed, it would likely be used to reduce the incidence of Alzheimer’s in people who carry genes that cause early-onset disease. People with certain genetic defects might also be candidates for the disease.
The earliest attempt to make this work was stopped in 2002 after participants in the trial developed inflammation of the brain. 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’s not ready for primetime, but there are active 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. “To get to large numbers of people who don’t normally make it into academic medical centres, you need something simple and safe,” Selkoe says.
If the drugs prove to be effective when they are administered before symptoms develop, then it might be helpful to use blood samples to identify people who would benefit from preventive treatment.
The drugs have side effects that can be serious. Reducing these will be key to shifting the risk–benefit equation in the drugs’ favour. 24.9% of people treated for lecanemab1 developed amyloid-related impairment, which is a brain swelling or bleeding disorder. Around 25% of people with ARIA experience confusion, headaches or dizziness. Seizures and even death are not very common.
The US Food and Drug Administration approved Lecanemab and donanemab. The decline in cognitive function is slow. Some clinicians think that individuals won’t notice a difference, but others think that a slow down will benefit a person with the disease and their family. Charlotte Teunissen, a neuroscience researcher at Amsterdam University Medical Center, says 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. Every year, there are about seven million new cases of Alzheimer’s in the United States.
Blood tests that can distinguish Alzheimer’s from other forms of dementia are one of the major breakthrough of the past five years. Although such diagnostics look set to become crucial tools for physicians and researchers, there are already concerns over their potential misuse, including by consumers.
Scientists’ understanding of Alzheimer’s continues to grow, and could lead to new avenues for treatment and prevention. A rare collection of genetic defects has inspired one line of attack. Evidence shows that pathogens could play a role in the development of Alzheimer’s. Researchers are also working on mechanisms behind differences in disease progression between genders, which could lead to better care for all. This work is under threat in the United States thanks to some funding cuts ordered by President Donald Trump. Alzheimer’s disease is a fight that can’t be taken lightly in the US.
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