Where Diseases Meet: A Cross-Comparison Between Alzheimer’s, Parkinson’s, and HIV-Associated Neurocognitive Disorder

Abstract

Up to 50% of people living with HIV who receive combined antiretroviral therapy develop HIV-Associated Neurocognitive Disorders (HAND), which clinically and neuropathologically resembles Alzheimer's Disease (AD) and Parkinson's Disease (PD) in symptoms of cognitive decline, memory impairment, motor dysfunction, and neuroinflammation. However, whether these conditions converge at the transcriptomic level remains poorly understood. This study performed differential expression analysis using Limma’s linear modeling with empirical Bayes variance shrinkage on three publicly available postmortem human brain transcriptomic datasets. Differentially expressed genes (DEGs) were identified for each disease relative to healthy controls using thresholds of |log₂ fold change| ≥ 0.25 and raw p < 0.05. DEGs were cross-compared at the gene level using pairwise Fisher's exact tests, and at the pathway level using Gene Ontology (GO) enrichment analysis via Enrichr, KEGG pathway analysis, and Gene Set Enrichment Analysis (GSEA). We found that HAND showed substantially more transcriptomic dysregulation than AD or PD. Gene-level overlaps were modest and not statistically significant after FDR correction, likely driven by DEG list size asymmetry. Despite this, pathway-level analysis revealed convergent neuroinflammatory patterns. Antiviral and immune activation pathways were enriched in HAND and PD but showed the opposite direction in AD, pointing to divergent immune microenvironments. These findings support the hypothesis that HAND shares partial but incomplete transcriptomic overlap with AD and PD, with neuroinflammatory convergence at the pathway level and disease-specific molecular features that may inform future biomarker discovery.