Characterizing Amyloid Pathogenic Spread in Alzheimer’s Disease Through A Network Diffusion Model

Early amyloid-<i>β</i> deposition is a hallmark of Alzheimer's disease (AD), though the exact nature of amyloid pathogenesis is not fully characterized. In this study, we designed a network diffusion model to simulate the spread of amyloid pathology through white matter brain networks of diagnostic subpopulations of healthy control (HC), mild cognitive impairment (MCI), and AD. Our network diffusion model was able to successfully model the spread of amyloid, recapturing regional distributions of amyloid observed in ¹⁸F-florbetapir positron emission tomography (r=0.44-0.46, P<0.01). When tuning the optimal parameters, we found that the optimal diffusion time (<i>t</i>) provided a notion of temporal progression, where the HC group had the lowest time (<i>t</i> = 107.22 ± 16.67), followed by MCI (<i>t</i> = 122.78 ± 19.63), and lastly AD (<i>t</i> =136.20 ± 24.47). The optimal starting seeds were the brainstem in all three diagnostic groups, followed by the lateral orbitofrontal lobes for HC and MCI and the lingual gyri in AD. Our findings corroborate evidence from amyloid staging studies where amyloid starts in the primary neocortex and associative cortex. The significance of the white matter structural network in the diffusion process provides evidence for the trans-synaptic spread hypothesis of amyloid in AD. In conclusion, our study provides novel insights into the pathogenesis of amyloid in AD and its subsequent propagation throughout the brain.