Rice University scientists say they have created the first complete, label-free molecular atlas of an Alzheimer’s brain in an animal model, combining hyperspectral Raman imaging with machine learning to map chemical changes that appear unevenly across brain regions and extend beyond amyloid plaques.
Scientists at Rice University report they examined brain tissue from both healthy animals and animals with Alzheimer’s disease to create a label-free molecular atlas of the brain.
To do that, the team used hyperspectral Raman imaging, a laser-based method that detects the chemical “fingerprints” of molecules. Because the approach is label-free, the tissue samples were not treated with dyes, fluorescent proteins or molecular tags, the researchers said.
“Traditional Raman spectroscopy takes one measurement of chemical information per molecular site,” said Ziyang Wang, an electrical and computer engineering doctoral student at Rice and a first author of the study. “Hyperspectral Raman imaging repeats this measurement thousands of times across an entire tissue slice to build a full map. The result is a detailed picture showing how chemical composition varies across different regions of the brain.”
The researchers said they mapped whole brains slice by slice, collecting thousands of overlapping spectra to generate high-resolution molecular maps of healthy and diseased tissue.
To analyze the large volume of imaging data, the team applied machine-learning methods, first using unsupervised approaches to identify patterns in molecular signals and then supervised models trained on known Alzheimer’s and non-Alzheimer’s samples to gauge how strongly different brain regions reflected Alzheimer’s-related chemistry.
“We found that the changes caused by Alzheimer’s disease are not spread evenly across the brain,” Wang said. “Some regions show strong chemical changes, while others are less affected. This uneven pattern helps explain why symptoms appear gradually and why treatments that focus on only one problem have had limited success.”
According to the researchers, the results suggest Alzheimer’s-related chemical changes are not confined to amyloid plaques and include broader metabolic differences. They reported that cholesterol and glycogen levels varied across regions, with the largest contrasts in memory-linked areas including the hippocampus and cortex.
“Cholesterol is important for maintaining brain cell structure, and glycogen serves as a local energy reserve,” said Shengxi Huang, an associate professor at Rice and a corresponding author of the study. “Together, these findings support the idea that Alzheimer’s involves broader disruptions in brain structure and energy balance, not only protein buildup and misfolding.”
The study was published in ACS Applied Materials and Interfaces. The research was supported by the National Science Foundation, the National Institutes of Health and the Welch Foundation, the Rice University release said.
Wang said the effort began with measurements from small areas of brain tissue and later expanded to full-brain mapping after multiple rounds of testing to integrate the measurements and analysis.
