Damaged Proteins Accumulate in Aging Brains

Study finds synaptic proteins more susceptible to breakdown issues in older brains, potentially contributing to cognitive decline

Feb. 3, 2026 at 1:31am

Got story updates? Submit your updates here. ›

Researchers have discovered that as we age, synaptic proteins in the brain break down much more slowly, become more likely to form tangled clumps, and are more likely to be taken up by microglia, the brain's immune cells. This age-related "garbage disposal" problem may help explain why synapses, the connections that wire up the brain, are among the first casualties of neurodegenerative diseases like Alzheimer's.

Why it matters

The findings shed light on the links between the brain's waste management systems, microglia, and neurodegeneration, potentially yielding new insights into human brain aging and conditions like Alzheimer's. The discovery that synaptic proteins are particularly vulnerable to this breakdown process could help explain why synapses are among the first things to be lost in neurodegenerative diseases.

The details

The researchers used a new tagging method to track the lifespan of neuronal proteins in young, middle-aged, and old mice. They found that in older mice, proteins took twice as long on average to be broken down and recycled compared to younger mice. Proteins were also more likely to clump up into plaque-like aggregates in older mice. The team discovered that synaptic proteins were more likely to degrade slowly and spill over into microglia, where many ended up in lysosomes, the cellular machines that break down proteins. This could disrupt microglial function and lead to synapse loss.

  • The study was published on January 21, 2026 in the journal Nature.
  • The researchers looked at protein lifespans in young adult mice (4 weeks old), middle-aged mice (12 months old), and old mice (24 months old).

The players

Ian Guldner

The lead author of the study, an instructor in the Department of Neurology and Neurological Sciences at Stanford Medicine.

Tony Wyss-Coray

The senior author of the study, the D.H. Chen Professor of Neurology and Neurological Science at Stanford Medicine and the Director of the Knight Initiative for Brain Resilience.

Carolyn Bertozzi

The Baker Family Director of Sarafan ChEM-H and the Anne T. and Robert M. Bass Professor in the Stanford School of Humanities and Sciences, who collaborated on developing the protein tracking tools used in the study.

Monther Abu-Remaileh

A Sarafan ChEM-H Institute Scholar and an assistant professor of chemical engineering in the School of Engineering and of genetics in the School of Medicine, who collaborated on the research related to lysosomes.

Got photos? Submit your photos here. ›

What they’re saying

“We know that cognitive function and synapse density both decrease in aging human brains. We also see that microglia grow more dysfunctional with age. If microglia are taking in synapses' damaged proteins, that could be overwhelming microglia and causing them to become dysfunctional. Overall, it would be a detrimental effect to brain health.”

— Ian Guldner, Lead Author

“If we can leverage our system to study neuron-derived proteins in the blood during aging and disease, we could potentially identify new biomarkers of brain health.”

— Ian Guldner, Lead Author

What’s next

The researchers plan to further investigate the link between damaged neuronal proteins, microglial dysfunction, and synapse loss, with the goal of identifying potential new biomarkers and therapeutic targets for neurodegenerative diseases.

The takeaway

This study provides important insights into how the brain's waste management systems break down with age, potentially contributing to cognitive decline and the onset of neurodegenerative diseases. The discovery that synaptic proteins are particularly vulnerable to this age-related 'garbage disposal' problem could help explain why synapses are among the first casualties in conditions like Alzheimer's.