Background <p>Alzheimer’s disease (AD) and Parkinson’s disease (PD) are complex neurodegenerative disorders with common pathological features, but the molecular mechanisms underlying their early stages remain poorly understood. This study aims to elucidate common and divergent changes in cellular processes in the early stages of neurodegeneration and neuroinflammation using brain organoid models.</p> Methods <p>We performed a multi-level comparative analysis of single-cell RNA sequencing data from brain organoid models previously designed to mimic specific features of PD- and AD-like pathology, by integrating gene expression, pathway enrichment, molecular network, and cell-cell communication analyses. Given the critical role of neuroinflammation in neurodegenerative disorders, we particularly focused on inflammatory signaling pathways and alterations in cell-cell communication that might drive disease progression.</p> Results <p>Our results reveal both common and contrasting changes between the different organoid models, including a common dysregulation of apoptotic pathways in astrocytes, a common upregulation of energy metabolism pathways in neurons, and opposing trends in ribosome-related pathways. Notably, our multi-level analysis identified key inflammatory alterations, including contrasting changes mediated by <i>HMGB1</i> and shared dysregulation in the <i>MDK</i> signaling pathway. Finally, comparison with <i>post-mortem</i> brain tissue and GWAS data revealed a small set of overlapping significant genes, showing robust shared patterns across different stages of pathology and tissue sources.</p> Conclusions <p>These findings provide new insights into the molecular basis of neurodegeneration and neuroinflammation, highlighting diverging and shared alterations between different organoid models and post-mortem brain tissues that may inform follow-up validation and preclinical intervention studies for neurodegenerative disorders.</p>