# Proteome Signature of Alzheimer-Like Phenotypes in Frontal Cortices From Young and Old Individuals With Down Syndrome

## TL;DR

This study identifies proteome signatures in the brains of individuals with Down syndrome that are linked to Alzheimer-like changes, highlighting age-related shifts in protein expression.

## Contribution

The study reveals specific proteome signatures in Down syndrome brains associated with Alzheimer's development, emphasizing age-related changes.

## Key findings

- Down syndrome brains show distinct proteome signatures linked to Alzheimer's disease development.
- Age-related shifts in protein expression accelerate neurodegeneration in Down syndrome.
- Key affected pathways include energy metabolism, synaptic transmission, and stress response.

## Abstract

Down syndrome (DS) stands out as the most prevalent genetic contributor to intellectual disability, marked by the presence of an extra copy of chromosome 21 (HSA21). Notably, individuals with DS exhibit significant neuropathological changes for a diagnosis of Alzheimer’s disease (AD), typically by the age of 50 years. To search for and identify biomarkers crucial for detecting and understanding the mechanisms involved in DS neuropathology, we conducted a protein expression analysis of post-mortem brain samples. We evaluated the frontal cortex of post-mortem brain samples from patients with DS both before and after the onset of AD pathology (DSAD), in comparison with age-matched healthy patients (CTRY and CTRO). Employing a comprehensive label-free shotgun proteomics approach, we sought to gain a deeper understanding of the intricate protein profiles associated with DS and its progression into DSAD. Collected results have been analyzed using specific databases and bioinformatics analysis software to understand relevant pathways, networks, and functions related to the experimental data. Our data support a genotype effect in DS at young and old ages that promotes specific proteome signatures associated with AD development. Notably, the affected signalling pathways encompass energy-related processes, synaptic transmission, and stress response. With aging, the dynamic shift in protein expression contributes to accelerating the neurodegenerative process, culminating in the manifestation of the AD phenotype.

The online version contains supplementary material available at 10.1007/s12035-025-05432-0.