Basic Science and Pathogenesis.

Background: Down syndrome (DS) is strongly associated with Alzheimer's disease (AD), attributable to APP overexpression, displaying common features with early-onset AD (EOAD) and late-onset AD (LOAD) like Amyloid-β (Aβ) and tau pathology. Here, we evaluated the Aβ plaques proteome of DS, EOAD and LOAD.

Method: We used unbiased localized proteomics to analyze amyloid plaques and the adjacent plaque-devoid tissue ('AD non-plaque') from post-mortem paraffin-embedded tissues in three subtypes of AD (n = 20/group): DS (59.8 ±4.99 y/o), EOAD (63 ±4.07 y/o), and LOAD (82.1 ±6.37 y/o). Functional associations were analyzed using Gene Ontology (GO) enrichment and protein interaction networks.

Result: We identified 132, 192 and 128 differentially abundant proteins in DS, EOAD and LOAD Aβ plaques (FDR<5%, fold-change<1.5). Common plaque-associated proteins constituted 14% across all groups, with 15% only in DS, 32% in EOAD, and 17% in LOAD. Significant correlations (p<0.0001) existed between DS and EOAD (R2 = 0.77) and DS and LOAD (R2 = 0.73), compared to EOAD and LOAD (R2 = 0.67). Top BP GO terms (p<0.0001) were lysosomal transport, regulation of the immune system process and lysosome organization for DS, EOAD and LOAD, respectively. Protein networks revealed a characteristic signature across all AD subtypes involving APP metabolism, immune response, and lysosomal pathways. We identified 263, 269, and 301 differentially abundant proteins in DS, EOAD and LOAD non-plaques. Common differentially abundant proteins constituted 12% across AD subtypes, with 24% only in DS, 14% in EOAD and 26% in LOAD. DS correlated significantly (p<0.0001) with EOAD (R = 0.59) and with LOAD (R = 0.33), compared to EOAD and LOAD (R = 0.79). The top BP GO term for all three subtypes was chromatin remodeling (p = 0.0013, p = 5.79 × 10, and p = 1.69 × 10, respectively). Additional GO terms for DS included extracellular matrix and integrin-mediated signaling (p = 0.0068), while EOAD and LOAD were associated with protein-DNA complexes and regulation of gene expression (p<0.0001).

Conclusion: We identified proteome differences in Aβ plaques across AD subtypes. Correlation and functional analyses revealed that DS and LOAD plaque-associated proteins primarily participate in lysosomal pathways, while EOAD proteins are linked to immune response. In contrast, EOAD and LOAD non-plaque proteins correlated better compared to DS, with functional differences reflected in the top GO terms.