Distinct fiber-specific white matter reductions pattern in early- and late-onset Alzheimer’s disease

Background: Early-onset Alzheimer’s disease (EOAD) has more domain cognitive deficits and worse prognosis than late-onset Alzheimer’s disease (LOAD). However, changes to white matter fiber pathways subserving the structural networks are still unclear, mainly due to the difficulty of modeling crossing-fiber populations. Thus, we used the recently established method, fixel-based analysis (FBA), to investigate fiber-specific white matter (WM) reduction patterns in EOAD and LOAD. Methods We identified 31 EOAD, 45 LOAD, 64 younger and 46 healthy elder controls (YHC/OHC). To repeat results, we further performed FBA in the ADNI database, including 17 EOAD, 30 LOAD, 31 YHC, and 34 OHC. Each subject underwent diffusion MRI scanning and neuropsychological assessments. Subjects from the ADNI database additionally underwent florbetapir and flortaucipir-PET examination. We measured the fiber density (FD) and fiber bundle cross-section (FC), then compared patients versus their counterparts (FWE corrected, P < 0.05). According to fixel-wise results, we further performed the tract of interest analyses. Results In the ZJU database, EOAD had decreased FD in the splenium of CC (SCC), limbic tracts, cingulum bundles, and posterior thalamic radiation (PTR), and decreased FC in the SCC, dorsal cingulum and PTR. By contrast, LOAD had comparable FD and FC decrease, centered to the SCC, cingulum bundles, and posterior association tracts. Both EOAD and LOAD had a similar decrease in FDC, mainly involving the cingulum bundle. Importantly, we found similar trends in the ADNI database. Correlation results showed that both the FD and FC were related to multiple cognitive performance and disease severity. Further, FD of fornix column and body and FC of ventral cingulum correlated with composite amyloid (r = -0.34) and tau level (r = -0.53) reflected by PET imaging, respectively. Conclusions Distinct WM damage in EOAD and LOAD might account for different cognitive pictures. Further, FD and FC might reflect different pathophysiological processes.