Atlas Finds Over 1,000 Hidden Microproteins Active in Alzheimer's Brain Tissue

A new catalog built from more than 600 postmortem frontal cortex samples reports 1,067 previously unannotated small proteins, some altered in Alzheimer's disease independent of the genes long thought to be their only product.

Researchers at the Salk Institute have published a new atlas of "microproteins", small proteins of 150 amino acids or fewer that are routinely missed by standard genome annotation, found active in the human frontal cortex. The study, led by Brendan Miller and Alan Saghatelian and published in Nature Aging on September 14, 2026, analyzed 608 postmortem frontal cortex samples from people with and without Alzheimer's disease, drawing heavily on tissue made available through the Religious Orders Study and Memory and Aging Project. Combining mass spectrometry, transcriptomic data and a deep-learning tool the team built called ShortStop, the researchers detected 4,321 candidate microproteins, of which 3,217 were absent from the standard human protein reference catalog, UniProtKB/Swiss-Prot; after ranking 3,001 of these by confidence, 1,067 met a high-confidence threshold for having been genuinely translated in brain tissue.

A subset of these microproteins was found at different levels in Alzheimer's disease tissue compared with tissue from people without the disease, and this difference held even when the expression of the larger, well-known gene sharing the same stretch of DNA did not change, the paper reports. One example singled out by the authors is a 63-amino-acid microprotein arising from the MKKS gene locus, whose canonical, much larger protein product is unrelated in size or known function. In postmortem brain tissue this microprotein, not the canonical MKKS protein, was the dominant translation product detected at that locus, and it was found at lower levels in Alzheimer's disease samples. In a cultured human microglial cell line, the researchers report, removing the gene segment encoding this microprotein reduced basal and maximal mitochondrial oxygen consumption, indicating a role in the energy metabolism of microglia, the brain's resident immune cells.

Outside researchers described the work as opening a layer of brain biology that proteomic and genomic surveys have largely missed. Bahareh Ajami, a neuroimmunologist at Cedars-Sinai Medical Center who was not involved in the study, said scientists "might be actually missing a whole layer of biology by overlooking these microproteins." Saghatelian himself urged caution about over-interpreting the catalog, noting that an altered microprotein could simply mark a disrupted gene rather than act on its own. The dataset has been made publicly available so other laboratories can attempt to validate individual microproteins and test their function directly.

The atlas itself does not establish what most of the 1,067 microproteins do; the MKKS finding is one functional example the authors chose to follow up, out of more than a thousand candidates now open to study.