Progressive memory circuit impairments along with Alzheimer’s disease neuropathology spread: evidence from in vivo neuroimaging

Background: Along with Alzheimer’s disease (AD) continuum, AD neuropathologies propagate trans-neuronally, causing the memory circuit disorganization and memory deficit. However, no evidence supports the hypothesis in vivo to date. Methods Based on biological diagnosis criteria, we divided subjects into 5 groups by setting the CSF cutoff point at 192 pg/ml for Aβ 1-42 (A) and 23 pg/ml for P-tau 181 (T): Group 0, cognitively normal (CN) with normal Aβ 1-42 and P-tau 181 (A−T−); Group 1, CN with A+T−; Group 2, CN with A+T+; Group 3, mild cognitive impairments (MCI) with A+T+; Group 4, AD with A+T+. We defined the memory circuit as the hippocampus (HP), cingulum-angular bundles (CAB), and precuneus cortex, respectively representing the starting point, core connecting fiber, and connected downstream cortex. Then we assessed the HP subfields volume, CAB diffusion metric (whole tract-level and waypoint-wise), and precuneus volume. Finally, we correlated neuroimaging measures with cognitive and neuropathological data. Results Along AD continuum, HP subfields volume initially increased and then decreased, starting from the early stage (CN with A+T-). CAB integrity loss on both whole tract-level and waypoint-wise in MCI and AD with A+T+ and progressed along AD continuum. Regarding precuneus, we only found the decreased volume in MCI and AD with A+T+, with CN stage spared. Further, memory circuit structure impairment correlated with more AD neuropathology and worse memory profile. Conclusion Our results support the tau propagation theory in the memory circuit, suggested that the memory circuit impairments starting from the HP, then propagating to the downstream projection tract and cortex.