Changing the balance between longer and shorter strings of amyloid- plaques to fight Alzheimer’s disease: a new approach based on the peptide pathway

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 long forms catalyse aggregation, so we need to shift the ratio of long over short,” says De Strooper.

Future treatments are going to have a big impact. clearing amyloid- plaques will never stop the disease because it doesn’t address the underlying problem, like vacuuming up wood dust from the floor. He says that it might make you feel better in the short term, but that it’s not going to help a person breathe more easily. Others see the logic in this thinking. “If the clearance mechanisms are the primary things that go wrong, then we’ve got to rescue them,” says Rubinsztein.

The group led by Nixon found brain tissue from people with Alzheimer’s disease that had bulging lysosomes spilling waste into the brain. lysosomes are insufficiently acidic to degrade molecule, and that seems to be the crux of the problem.

Alzheimer’s is also associated with tangles of thephosphorylcholine that are inside the brain. Most people think that the development of the tangles is related to the amyloid- pathology, but that doesn’t mean they can put the brakes on it. At some point, the pathology could become self-sufficient and continue to grow. “You can remove amyloid, but you won’t stop that process,” says De Strooper.

The drug being developed by the Swiss pharmaceutical company is doing well in early-stage trials. The toxicity seems to have been overcome, and they didn’t see any mechanistic side effects. If it works, this approach could make a cheap pill a reality. Selkoe said that the -secretase was going to become the main cause of Alzheimer’s disease in the future.

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. The APP is slice in two places by two enzymes, creating amyloid-. Small molecules to target these enzymes could stop plaques from forming.

If a vaccine was developed, it would probably be used to prevent Alzheimer’s in people who have a genetic link to the disease. The more common form of the disease might be possible if a person with a certain genetic defect is also involved.

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. Researchers are getting back to the idea that part of the vaccine caused a response by a type of white blood cell called the T cell and how to prevent it. “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 is cheaper and straightforward than anti-rejection injections. “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 more effective when administered before symptoms develop, advances in monitoring the development of pathology using biomarkers in the blood might be key to identifying, cheaply, people who would benefit from preventive treatment.

The drugs also have side effects, which are occasionally serious. The risk–benefit equation can be changed if these are reduced. More than 20% of people who received lecanemab1 developed brain swelling or bleeding. This is usually asymptomatic, but around one-quarter of people with ARIA experience confusion, headaches or dizziness. Even death is not uncommon butSeizures and even death are rare.

The FDA approved donanemab and lecanemab once in the next 20 years. Both slow cognitive decline by around 30%. 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. A 30% lesser decline does mean something, says Charlotte Teunissen of Amsterdam University Medical Center. She says the difference between having meaningful conversations with your children and not is six months longer in a coherent state.

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. It is sad but there are seven million new cases of Alzheimer’s every year.

The past five years have seen a variety of new developments, the most significant being the development of blood tests that can differentiate Alzheimer’s from other forms of dementia. Concerns over their potential misuse are already in place, despite the fact that these diagnostics look set to become crucial tools for physicians and researchers.

Scientists’ understanding of Alzheimer’s continues to grow, and could lead to new avenues for treatment and prevention. A woman from rural Colombia with a rare collection of genetic mutations has inspired one line of attack. There is mounting evidence that the development and progression of Alzheimer’s may be related to pathogens. The mechanisms behind the differences in disease progression between the sexes could lead to better care for all. However, this work now finds itself under threat in the United States, with some funding cuts ordered by President Donald Trump’s administration. Alzheimer’s disease is not safe from US politics.

We are grateful to Eli Lilly & Company for their financial support of this Outlook. Nature is the only one who has sole responsibility for editorial content.