Morphological connectivity differences in Alzheimer's disease correlate with gene transcription and cell-type

Alzheimer's disease (AD) is one of the most prevalent forms of dementia in older individuals. Convergent evidence suggests structural connectome abnormalities in specific brain regions are linked to AD progression. The biological basis underpinnings of these connectome changes, however, have remained elusive. We utilized an individual regional mean connectivity strength (RMCS) derived from a regional radiomics similarity network to capture altered morphological connectivity in 1654 participants (605 normal controls, 766 mild cognitive impairment [MCI], and 283 AD). Then, we also explored the biological basis behind these morphological changes through gene enrichment analysis and cell-specific analysis. We found that RMCS probes of the hippocampus and medial temporal lobe were significantly altered in AD and MCI, with these differences being spatially related to the expression of AD-risk genes. In addition, gene enrichment analysis revealed that the modulation of chemical synaptic transmission is the most relevant biological process associated with the altered RMCS in AD. Notably, neuronal cells were found to be the most pertinent cells in the altered RMCS. Our findings shed light on understanding the biological basis of structural connectome changes in AD, which may ultimately lead to more effective diagnostic and therapeutic strategies for this devastating disease.