Scientists Map How Alzheimer's Begins in the Brain

Newsweek

18 hours ago

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In an unprecedented large-scale study, researchers have mapped out the first molecular events that cause harmful protein buildups in the brain of people with Alzheimer's disease.
"By measuring the effects of over 140,000 different versions of proteins, we have created the first comprehensive map of how individual mutations alter the energy landscape of amyloid beta aggregation—a process central to the development of Alzheimer's disease," said paper author and computational biologist Anna Arutyunyan of the Wellcome Sanger Institute in a statement.
"Our data-driven model offers the first high-resolution view of the reaction's transition state, opening the door to more targeted strategies for therapeutic intervention," Arutyunyan added.
The Alzheimer's Association estimates that some 7.2 million Americans aged 65 and older are presently living with the disease. Its first outward symptom is typically memory problems, but it can lead to delusions, speech issues, disturbed sleep and mood swings.
Artist's impression of amyloid-beta peptide buildups within the brain.
Artist's impression of amyloid-beta peptide buildups within the brain.
selvanegra/iStock / Getty Images Plus
At the heart of more than 50 different neurodegenerative diseases is the molecule amyloid beta. This peptide (a chain of amino acids) has a tendency to clump together, forming structures known as amyloid fibrils.
In turn, these fibrils gather together into so-called "plaques"—which play a central role in the progression of Alzheimer's disease.
The transition from free-flowing amyloid beta to stable fibril structures requires a certain amount of energy—with the peptides having to pass through a "transition state."
This state is extremely unlikely to form, accounting for why fibrils and plaques never form in most people. It is also extremely short-lived, which helps account for how difficult it is to study how amyloid beta starts aggregating.
Nevertheless, understanding these molecular structures and reactions will be vital for the future development of therapies against Alzheimer's and similar conditions.
In the new study, Arutyunyan and colleagues probed the amyloid beta transition by exploring how changing the genetics of the peptide affects its aggregation rate.
The team focused on Aβ42, a form of the amyloid beta with 42 amino acids that is commonly found in people with Alzheimer's disease.
The researchers used three techniques in their work. First, "massively parallel sequencing" allowed the team to see how changing the amino acids in Aβ42 affects the amount of energy needed to form a fibril.
Next, they used genetically engineered yeast cells to measure the rate of the aggregation reaction. Finally, the team used machine learning tools to analyze the results and map out the effect of all the possible mutations of the peptide on fibril formation.
In total, the team were able to assess more than 140,000 versions of Aβ42 in one pop—a breakthrough in scale that boosts the accuracy of the resulting models.
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The analysis revealed that only a very few specific interactions between parts of the amyloid beta peptide strongly influenced the rate of fibril formation.
Furthermore, the team found that the aggregation reaction begins at one of the tightly packed, water-repellent ends of the peptide, which is known as the C-terminal region.
Accordingly, the researchers hope that targeting interactions in this region might allow new means to protect against and treat Alzheimer's disease.
"The approach we used in this study opens the door to revealing the structures of other protein transition states, including those implicated in other neurodegenerative diseases," said genomicist professor Ben Lehner, also of the Wellcome Sanger Institute, in a statement.
"The scale at which we analyzed the amyloid peptides was unprecedented … we have shown it's a powerful new method to take forward.
"We hope this takes us one step closer to developing treatments against Alzheimer's disease and other neurodegenerative conditions," Lehner added.
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Reference
Arutyunyan, A., Seuma, M., Faure, A. J., Bolognesi, B., & Lehner, B. (2025). Massively parallel genetic perturbation suggests the energetic structure of an amyloid-β transition state. Science Advances, 11 (24). https://doi.org/10.1126/sciadv.adv1422