Tiny protein oligomers may unlock earlier diagnosis for Alzheimer's and related diseases

by Birgitte Svennevig, University of Southern Denmark

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For more than three decades, scientists have sought to combat diseases caused by protein misfolding by targeting the large protein clumps that accumulate in affected tissues. Yet, despite intensive efforts, clinical success has been limited.

Protein-misfolding diseases include many difficult-to-cure diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS and even type 2 diabetes.

A new review by researchers from the University of Southern Denmark and Kent State University suggests that future breakthroughs in treating protein-misfolding diseases may come from targeting tiny protein aggregates known as oligomers, which form early in the disease process. They are increasingly believed to drive cellular damage.

The review is published in Nature Reviews Chemistry. The authors are postdoctoral researcher Pernille Vosbein and associate professor Chenguang Lou from the Department of Physics, Chemistry and Pharmacy at the University of Southern Denmark, and professor Hanbin Mao from the Department of Chemistry and Biochemistry at Kent State University.

Protein-misfolding diseases differ in symptoms and affected organs, but they share a common feature: Proteins lose their normal structure, misfold and begin to aggregate, also known as clumping. Traditionally, research has focused on the large deposits that eventually form.

"Increasingly, however, scientists are beginning to suspect that the smaller oligomers formed earlier in the aggregation process may be the most damaging species," said co-author Lou.

A shift in Alzheimer's research

For many years, the dominant view was that the large protein deposits found in affected tissues were the primary drivers of disease. In Alzheimer's disease, for example, research focused heavily on amyloid-beta plaques, large aggregates of amyloid-beta protein that accumulate in the brain. Yet, despite decades of work, therapies directed at these deposits have delivered only limited clinical benefits.

These disappointing results prompted researchers to ask whether the most harmful events occur much earlier, before amyloid plaques form. Increasing evidence suggests that small protein aggregates known as oligomers may be more toxic than the larger deposits that eventually form. Because oligomers appear early in many disease processes, they are increasingly being investigated as both therapeutic targets and potential biomarkers for early diagnosis.

Although the review covers many protein-misfolding disorders, Alzheimer's disease remains the most extensively studied model system. The disease affects approximately 55 million people worldwide and is characterized by two hallmark pathological features: amyloid-beta plaques outside neurons and tau tangles inside neurons.

For decades, these plaques and tangles have dominated research and drug development efforts. However, increasing evidence suggests that substantial damage may occur before these large structures become established. Small amyloid-beta oligomers appear earlier in the disease process and have been linked to synaptic dysfunction, memory impairment, inflammation and neuronal damage.

Some researchers now believe that plaques may form after much of the cellular damage has already begun. They may even act as reservoirs for smaller toxic aggregates rather than being the primary drivers of damage themselves.

Disrupting communication between nerve cells

According to the authors, the attraction of oligomers as therapeutic targets lies in their position early in the disease process.

Research in Alzheimer's disease suggests that these small aggregates can disrupt communication between nerve cells long before extensive plaque formation becomes visible. Similar toxic aggregates have also been implicated in Parkinson's disease, where α-synuclein forms oligomers; in Huntington's disease through huntingtin oligomers; and in ALS through proteins such as SOD1 and TDP-43.

"If scientists can identify which oligomers are truly harmful, they may be able to intervene at a much earlier stage of disease development. Their abundance could also enable early diagnosis," said co-author Mao.

The problem is that oligomers are notoriously difficult to study.

They exist only transiently, occur at very low concentrations and constantly change in size and structure. Many traditional laboratory methods either fail to detect them or alter them during analysis.

As a result, researchers have spent the past two decades developing increasingly sophisticated analytical methods capable of observing individual oligomers. These include advanced mass spectrometry, atomic force microscopy, nanopore sensing and single-molecule approaches that can monitor individual protein assemblies one molecule at a time.

According to the authors, the next major challenge is to determine exactly which oligomers drive disease in patients and how they can be detected reliably in biological samples such as blood, cerebrospinal fluid or brain tissue.

"If successful, the field could move from treating the visible end products of Alzheimer's disease to intervening at the disease-causing molecular events that drive it," Lou said.

More information

Pernille Vosbein et al, Targeting soluble misfolded oligomers in anti-amyloid research, Nature Reviews Chemistry (2026). DOI: 10.1038/s41570-026-00867-y

Key medical concepts

Alzheimer's Disease

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Neurology Provided by University of Southern Denmark Who's behind this story?

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