Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment

Background: The roles of amyloid-beta and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [F-18]AV-45 and [F-18]AV-1451 PET quantify amyloid-beta and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. Objective: Examine the impact of amyloid-beta and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. Methods: Combined [F-18]AV-45 and [F-18]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. Results: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p < 0.05). Hippocampal strength inversely correlated with [F-18]AV-1451 SUVr in MCI (r = -0.55, p = 0.049) and AD (r = -0.57, p = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [F-18]AV-45 SUVr in those same regions in MCI (r = -0.33, p = 0.003) and AD (r = -0.31, p = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r = -0.60, p = 0.035) and left hippocampus in AD (r = 0.69, p = 0.024). Clinical Dementia Rating Scale scores correlated with [F-18]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r = 0.65, p = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r = 0.062, p = 0.009) parahippocampal gyrus in AD. Conclusion: Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-beta in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.