Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease

The relationships between β-amyloid (Aβ), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aβ PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aβ PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, ¹¹C-PiB (Aβ) PET and ¹⁸F-AV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. ¹¹C-PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas ¹⁸F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p<0.05 Family-Wise Error-[FWE]-corrected). Voxel-level analysis identified negative correlations between ¹⁸F-AV1451 and gray matter peaking in medial and infero-occipital regions (p<0.01 False Discovery Rate-[FDR]-corrected). ¹⁸F-AV1451 and ¹¹C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p<0.001 uncorrected). ¹¹C-PiB did not correlate with GMR at the voxel-level. Regionally, ¹⁸F-AV1451 was largely associated with local/adjacent GMR whereas frontal ¹¹C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between Aβ and neurodegeneration are not region specific and may be mediated by the interaction between Aβ and tau.