Transcriptomic Similarity Reveals Neuroanatomical Differences Among Alzheimer's Disease Subtypes

The complexity of Alzheimer's disease (AD) is influenced by population heterogeneity, prompting the study of subtypes through imaging phenotypes. However, the role of neural morphological heterogeneity and the correlated gene expression (CGE) in AD subtypes remains unclear. This study links cortical thickness deviations of AD subtypes with CGE connectivity patterns. Transcriptional activity was measured based on the Allen Human Brain Atlas, and a density-based clustering algorithm identified AD subtypes. Subtype 1 mainly exhibits cortical thinning, while subtype 2 shows cortical thickening. Using whole-brain gene expression data, we found that deviations in transcriptionally connected neighboring regions predicted regional deviations in both subtypes. Gene enrichment analysis revealed that epicenter regions were associated with biological processes like synaptic dysfunction and phosphorylation regulation. Our study establishes associations between CGE connectivity and neural morphological alterations, identifies distinct epicenter regions in AD subtypes, and provides novel insights into how molecular-level gene expression shapes subtype-specific pathology.