Initial levels of β-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimer’s disease

Abstract

Background Clarifying the relative roles of β-amyloid (Aβ) plaques and tau tangles in longitudinal tau replication and propagation inside and outside the medial temporal lobe (MTL) as well as how age, sex, APOE-4, and Klotho-VS heterozygosity (KL-VShet) modulate their relationships in Alzheimer’s disease (AD) may help with designing therapeutic clinical trials for AD and aid in our understanding of the disease’s symptoms. Methods We divided the 325 Aβ PET positive (A+) participants in this study into two groups, A+/T- (143) and A+/T+ (182), based on the threshold (1.25) of the Temporal-metaROI 18F-flortaucipir (FTP) standardized uptake value ratio (SUVR). We compared the baseline and slopes of A+/T- and A+/T + individuals’ Aβ plaques and Temporal-metaROI tau tangles with those of 162 A-/T- cognitively normal individuals without neurodegeneration. We also looked into how baseline Aβ and tau predict longitudinal tau increases and how age, sex, APOE-4, and KL-VShet affect these associations. Results In entorhinal, amygdala, and parahippocampal (early tau-affected regions of Temporal-metaROI), we found baseline Aβ and tau deposition were positively linked with more rapid tau increases in A+/T- participants. However, in A+/T + individuals, the longitudinal tau propagation of the fusiform, inferior temporal, and middle temporal cortices (late tau-affected regions of Temporal-metaROI) was primarily fueled by the presence of tau tangles rather than Aβ plaques. Furthermore, compared to older people (age≥65), younger individuals (age≤65) had faster Aβ-dependent but slower tau-related tau accumulation. Additionally, compared to the KL-VShet− group, KL-VShet+ carriers showed significantly less longitudinal tau accumulation associated with baseline entorhinal tau in the fusiform and inferior temporal regions. Conclusion These findings offer novel perspectives on developing AD treatment plans and aid in understanding tau replication and propagation inside and outside MTL in AD. In particular, decreasing Aβ plaques might be adequate for A+/T- persons but may not be sufficient for A+/T + individuals in preventing tau propagation and subsequent downstream effects connected to tau.