Does Loss of Integrity of the Cingulum Bundle Link Amyloid-beta Accumulation and Neurodegeneration in Alzheimer's Disease?

Background: Alzheimer's disease is characterized by the accumulation of amyloid-beta (A beta) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial A beta deposition and local neurodegeneration. Objective: Here, we test the hypothesis that the cingulum bundle links A beta deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. Methods: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available A beta-PET scan, T1-weighted and diffusion-weighted MRI were included. A beta load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. Results: We found at most a weak association between cingulate A beta and MTL volume (added R-2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate A beta or MTL volume (added R-2 <0.01). Various sensitivity analyses (A beta-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. Conclusion: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus A beta deposition and MTL atrophy.