Researchers: Time to shift focus in the fight against Alzheimer’s and related diseases

“Kill your darlings” is a phrase we use when an idea that once seemed highly promising turns out not to be the solution we hoped for.

That is a difficult conclusion to reach, especially after decades of research built around the same hypothesis. Yet this is exactly the challenge posed by a new scientific review examining the diagnosis and treatment of so-called protein-misfolding diseases.

This group of diseases includes Alzheimer’s disease, Parkinson’s disease, ALS, Huntington’s disease and type 2 diabetes. They occur when proteins lose their normal structure, misfold and begin to aggregate. Depending on the disease, this process can take place in different organs throughout the body.

The true driver of disease?

What these diseases have in common is the buildup of misfolded proteins in affected tissues. A few treatments today have been developed with the aim of reducing or removing these protein buildups.

Such treatments may relieve symptoms or slow disease progression, but researchers have yet to develop effective drugs capable of preventing or curing these diseases. Nor do reliable methods exist for diagnosing them at an early stage or intervening before substantial damage has occurred.

Now, researchers from the University of Southern Denmark and Kent State University in the United States are calling for a shift in focus. Instead of concentrating on the large protein buildups, they argue that attention should turn to much smaller protein structures that may be the true drivers of disease.

30 years with modest results

The researchers outline findings in the field and perspectives in a review published in Nature Reviews Chemistry, "Targeting soluble misfolded oligomers in anti-amyloid research". The paper is available here.

“For more than 30 years, researchers have been working to develop effective treatments, but many of them largely address symptoms and provide only modest benefits. It is time to shift our focus,” says Associate Professor Chenguang Lou from the Department of Physics, Chemistry and Pharmacy.

The small protein structures at the centre of the review are known as oligomers. They emerge early in the disease process, long before larger and more visible protein buildups appear. Research in Alzheimer’s disease has already shown that oligomers can disrupt communication between nerve cells, trigger inflammation and contribute to memory loss and cell death.

If the concept works

“Increasing evidence challenges the traditional view that the large protein buildups are the primary driving force behind the disease,” says Chenguang Lou.

According to the authors, these larger accumulations may in some cases be a consequence of the disease process rather than its underlying cause. They may even serve as reservoirs that store the smaller, more harmful oligomers.

“If the concept works, we can move beyond simply treating the symptoms of protein-misfolding diseases and begin targeting the molecular mechanisms that actually drive them,” says Chenguang Lou.

Notoriously difficult to study

Oligomers are a promising target for future therapies, but studying them is far from straightforward. They are short-lived, present in extremely low concentrations and constantly changing in size and structure. Many conventional laboratory techniques either fail to detect them or risk altering them during analysis.

For this reason, the researchers are calling for stronger collaboration across scientific disciplines to develop new technologies and analytical tools that can reveal how oligomers behave and, ultimately, how they can be targeted by future medicines.

Since 2021, Chenguang Lou and his colleague and co-author of the review, Professor Hanbin Mao of Kent State University, have been working in this area through a research project funded by the Lundbeck Foundation.

Inspiring other researchers in the field

Their goal was to realize so-called de novo design of oligomers: laboratory-made versions of these tiny protein assemblies that can be used to understand how they can be formed and explore their potential use for drug discovery.

Within the past five years, the team has developed a new method and produced the first successful models. They now hope that the new review will help bring the field together around a new research direction.

“We want to highlight the importance of oligomers and encourage more research groups to invest their time, resources and expertise in this area. Only through a collective effort can we have the chance to develop more powerful diagnostic tools and more effective clinical solutions”, says Chenguang Lou.