The brain undergoes significant changes with age, but at what point does normal aging turn into a disease?
Researchers at Boston University (BU) School of Medicine developed a high-resolution mapping technique to identify these early disease-linked changes. Their study uncovered specific protein and sugar signatures that differentiate healthy aging from Alzheimer’s disease (AD) and Lewy body pathology.
The molecular link between aging and Alzheimer’s
Identifying brain disorders such as AD or Lewy body disease (LBD) usually happens too late; by the time a doctor confirms a diagnosis, the brain has already suffered irreversible damage. This diagnostic delay is a big hurdle in modern neurology.
Aging naturally changes how our brain functions, often leading to a buildup of misfolded proteins. While we know that aging is the primary risk factor for AD and LBD, the molecular clock that triggers this decline isn’t fully understood.
Glycosylation is the process by which sugars attach to proteins, helping them fold and remain stable. These sugars, along with the scaffolding between brain cells known as the extracellular matrix, are vital for healthy signaling. However, despite their importance, they are notoriously difficult to study.
Past research has struggled to capture high-resolution data from the small, specific regions of the brain where age-related changes first occur. Scientists often had to use large amounts of tissue, which blurred the fine details needed to spot early warning signs.
The team aimed to overcome these issues by developing a high-resolution workflow to map the precise molecular changes that happen throughout aging. Their goal was to identify the specific protein and sugar signatures that distinguish a healthy aging brain from one on the path toward Alzheimer’s.
The study focused on the temporal cortex, a brain region central to memory and often the first to show signs of decline.
Using spatial proteomics to map brain disease signatures
To solve the resolution problem, the team developed an innovative on-slide digestion method. Instead of grinding up large chunks of brain tissue, they worked with 5 mm circles of tissue mounted directly onto glass slides. They applied specialized enzymes to these circles to release proteins and sugars while keeping the spatial context intact. By using liquid chromatography data-independent acquisition-tandem mass spectrometry (LC-DIA-MS/MS), the team captured a more complete and consistent dataset of proteins, glycosylated proteins, and the extracellular matrix than previous methods allowed.
The team then analyzed these samples using advanced proteomics—a technique that measures thousands of proteins simultaneously to create a complete molecular map.
The study followed two paths. First, they looked at young and aged mice to define the baseline for “normal” aging. They then examined human brain tissue from patients with AD, including cases where the disease overlapped with LBD. This comparison was important since many patients suffer from both conditions, making it harder to provide the right treatment.
The team successfully extracted high-resolution data from these minimal tissue samples, identifying clear fingerprints for both proteins and sugars. They found distinct signatures that could differentiate between a healthy aging brain and one affected by disease, including changes in the extracellular matrix.
They also spotted specific molecular changes that appeared only when Lewy bodies were present, distinguishing pure AD from more complex cases.
Future clinical implications for Alzheimer’s diagnosis and treatment
These molecular fingerprints could eventually lead to diagnostic tools that detect brain disease years before the first signs of memory loss or movement problems appear. Identifying these shifts early could lead to interventions that might slow or even stop the progression of the disease.
“Our study elucidates how the brain changes with aging and with diseases such as AD in the presence or absence of Lewy body pathology at a highly detailed molecular level,” said corresponding author Dr. Manveen Sethi, an assistant professor at BU School of Medicine.
As this method requires so little tissue, it can be applied to many other diseases and diverse clinical samples, providing a blueprint for scientists to study how different regions of the body change over time.
“Understanding these changes is important because they begin years before symptoms such as memory loss or movement problems appear. Clinically, this work may help scientists discover new biomarkers to support earlier diagnosis, improved disease classification, or better treatment monitoring,” said Sethi.
However, translating results from mice to humans is always complex, and while the human data is promising, it was based on a small group of 14 individuals.
Larger studies are needed to confirm these specific biomarkers before they can be used in a clinic. Future work that includes longitudinal studies is also needed to see if these protein changes can track how well a treatment is working.
This could be the first step toward a new era of early detection.
Reference: Nigro JT, Chatterjee S, Freilich S, et al. Mass spectrometry analysis of young and aged mice and human Alzheimer’s disease with Lewy body pathology using on-slide tissue digestion. Anal Bioanal Chem. 2026. doi: 10.1007/s00216-026-06385-6
This article is a rework of a press release issued by Boston University School of Medicine. Material has been edited for length and content.