Microproteins provide new playbook for Alzheimer’s research

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Microproteins provide new playbook for Alzheimer's research

September 14, 2026

Salk Institute scientists create first microprotein atlas of human frontal cortex with and without Alzheimer's disease, then find link between a microprotein and brain immune cell dysfunction in Alzheimer's disease

September 14, 2026

• Highlights
• Salk researchers establish microprotein atlas from human frontal cortex samples with and without Alzheimer's disease, identifying more than 1,000 new microproteinsy
• The atlas reveals one microprotein that may contribute to age-related dysfunction in the brain's resident immune cells
• The publicly available resource will allow scientists to consider microproteins in their studies, lighting the path to new potential targets for neurodegenerative diseases
• The study may also be used as a framework for building additional microprotein atlases for other tissues and disease areas

LA JOLLA-Scientists researching Alzheimer's disease and neurodegeneration have been playing a difficult game. Their scientific playbook has been limited by the available resources that, while capturing loads of genes, proteins, and cells, have been missing something: microproteins.

Brendan Miller (left) and Alan Saghatelian (right) created the first microprotein atlas of the human frontal cortex with and without Alzheimer's disease, then used the atlas to find a link between a microprotein and brain immune cell dysfunction in Alzheimer's disease. The atlas was created with help from their AI-powered microprotein-finding tool, ShortStop, which can be seen on the computer.
Click here for a high-resolution image.
Credit: Salk Institute

A novel microprotein atlas, developed at Salk and assembled using human brain samples, adds a whole lot more to the playbook-giving scientists more to work with and a better chance at winning the fight against neurodegeneration. The team used 480 human frontal cortex samples with and without Alzheimer's disease to identify over 1,000 new microproteins and found a potential link between one microprotein and brain-resident immune cell dysfunction in Alzheimer's disease.

The study was published in Nature Aging on September 14, 2026, and was funded by both federal research grants from the National Institutes of Health and private philanthropy.

"We still do not fully understand the molecular mechanisms of healthy aging, and that is especially true for microproteins, which have been inadvertently overlooked for decades," says senior and co-corresponding author Alan Saghatelian, PhD, a professor and Dr. Frederik Paulsen Chair at Salk. "Our atlas allows scientists to systemically investigate microproteins in aging and neurodegeneration, which should bring us closer to understanding and tackling diseases like Alzheimer's or Parkinson's."

What are microproteins?

Every cell in our bodies holds the same genetic code-packed into an impressive two meters of DNA from end to end. But no one cell uses all this code. Instead, each cell refers to this code like a playbook, choosing which proteins to make from it.

The proteins each cell makes determine both behavior and identity, differentiating a brain cell from a heart cell from an immune cell. Knowing what proteins each cell makes then becomes incredibly important to understanding how that cell functions and why it might dysfunction. For scientists studying neurodegeneration and conditions like Alzheimer's disease, figuring out exactly what proteins brain cells use or don't use can point them to new predictors, preventions, and treatments.

While scientists have a good understanding of what proteins brain cells make, the same cannot be said for microproteins. Owing to their size, this smaller class of proteins is harder to both find and study, yet they play important roles in both health and disease. A new focus on identifying microproteins has revealed that brain cells do produce them. But which ones?

How do you create a microprotein atlas?

The Salk team used existing native transcriptomic and mass spectrometry data to jump right into identifying microproteins. They utilized ShortStop, an AI-powered tool created in Saghatelian's lab in 2025, to probe this wealth of data for microproteins in brain cells.

"We were able to take all these technologies and tools and reapply them to existing data from nearly 500 brains to find new microproteins," says the first and co-corresponding author Brendan Miller, PhD, a postdoctoral researcher in Saghatelian's lab. "We were able to create an entirely new database that researchers can download and use to better interpret functions of genes."

The atlas relied on data from 480 human brain frontal cortex samples, some with and some without Alzheimer's disease. By running this existing data through their own custom computer programs (including ShortStop), the Salk team identified 1,067 uncharacterized microproteins, many of which were never detected before the study.

What makes this atlas reliable is that these 1,067 microproteins were confirmed using a machine called a mass spectrometer, which physically detects the protein's building blocks (peptides). Because the physical microprotein evidence from the mass spectrometry data matched with their predictions, scientists can be confident that the microproteins exist.

With these new microproteins in hand, the scientists began to look for differences in their expressions between Alzheimer's disease brain cells and healthy ones.

How do microproteins differ between healthy and Alzheimer's disease brains?

The study revealed that hundreds of the newly discovered microproteins were expressed at different levels in Alzheimer's disease brain cells compared to healthy counterparts. While some microproteins were expressed more and some expressed less, Alzheimer's disease cells tended to have more microproteins expressed overall.

In addition to establishing the atlas and making these general observations, the Salk researchers also followed up more specifically within one type of brain cell in the human frontal cortex: microglia, the brain's resident immune cells. Microglia are abundant in brain cells and commonly dysfunction with age and in neurodegenerative diseases like Alzheimer's.

A microglial cell within which an uncharacterized microprotein (orange) accumulates around its nucleus (blue). A new Salk Institute microprotein atlas can help determine what microproteins are expressed in microglia, and whether they are involved in the health or dysfunction of the critical brain cells.
Click here for a high-resolution image.
Credit: Salk Institute

The team generated their own mass spectrometry data on microglia, looking for microproteins that may be differentially expressed in these cells. What they found highlighted the importance of their atlas: Within the same stretch of genetic code, a protein and microprotein could both be made. But here, the microglia were expressing the microprotein, not the protein.

When the team removed the microprotein-making gene in microglia, the cell's energy-making mitochondria became impaired. The findings suggest a link between the microprotein and dysfunctional microglia in Alzheimer's disease-a promising new avenue to consider in developing therapeutics that keep microglia healthy.

What is next for microproteins?

The Salk research findings were made possible by the volunteers who participated in the Religious Orders Study/Memory and Aging Project (ROSMAP) cohort. ROSMAP provided the researchers access to human frontal cortex samples, allowing them to utilize the clinical data to build their atlas. Similar research efforts in other brain regions using ROSMAP samples could eventually expand the atlas to encompass the entire brain.

While not every microprotein is involved in every disease, having a thousand more to consider gives scientists a better chance of identifying physiologically relevant microproteins for targeted interventions.

"Every coach has a playbook, and you want as many plays as possible to win the game," says Miller. "For scientists, the game is trying to understand the disease, and the plays are the proteins and microproteins that may or may not be involved in that disease."

"There is sometimes an assumption that we know everything about our genome, and we know all the genes our cells can make-that's just not true," says Saghatelian. "What we know is constantly expanding, and this atlas makes it that much easier to study microproteins in life science research."

Other authors and funding

Other authors include Eduardo Vieira de Souza, Calvin Lau, Joan Vaughan, Victor Pai, Servando Macias, and Andréa Rocha of Salk; Jolene Diedrich of Scripps Research Institute; and David Bennett of Rush University.

The work was supported by the National Institutes of Health (P30CA014195, R01GM102491, P30AG10161, R01AG15819, R01AG17917, RC2AG0365, AG062429) and Clayton Medical Research Foundation.

This press release was written by Isabella Davis.
Contact: [email protected]

DOI: 10.1038/s43587-026-01207-x