Amygdala shows heterogeneous atrophy and tauopathy patterns across the AD continuum

Abstract Background Amygdala shows early vulnerability in Alzheimer’s disease (AD), although its substructures have been less studied than hippocampal subfields. Neuropathological evidence suggests that tau pathology affects amygdala subnuclei differentially, yet in vivo characterization of subregional amygdala atrophy, its relationship with tau burden, blood-based biomarkers, and cognitive outcomes across the AD continuum remains limited. Clarifying whether amygdala degeneration follows a homogeneous or regionally selective pattern, how it relates to plasma tau biomarkers, and whether it has functional consequences is essential for improving early detection and disease modeling. Methods The study analyzed data from 197 participants, including 71 Aβ-negative cognitively normal individuals (Aβ − CN), 31 Aβ-positive cognitively normal individuals (Aβ + CN), and 95 Aβ-positive cognitively impaired individuals (Aβ + CI). All participants underwent T1-weighted MRI, [ 18 F]-MK-6240 tau PET imaging, comprehensive neuropsychological assessment, and plasma pTau181 and pTau217 and Aβ42/40 analyses. Amygdala subregion volumes and tau standardized uptake value ratios (SUVr) were extracted using FreeSurfer-based segmentation and classified into basal, centro-medial, and lateral amygdala subregions. Regional amygdala volumes and SUVr were compared across groups and examined for associations with plasma tau biomarkers and cognitive performance. Mediation analyses assessed whether subregional amygdala atrophy mediated the relationship between tau pathology and cognition. Results Pronounced regional heterogeneity was observed within the amygdala. Atrophy of the centro-medial subregion was detectable at the preclinical stage of AD, preceding cognitive impairment. This vulnerability was not associated with a higher local tau burden. However, lower centro-medial amygdala volume was significantly associated with higher plasma pTau181 and pTau217 levels, as well as with lower memory and executive scores. Mediation analyses demonstrated that centro-medial amygdala volume mediated the effect of tau pathology on memory performance. Conclusion These findings suggest that amygdala involvement in AD is regionally heterogeneous, appears early in the AD continuum, and has clinically significant cognitive consequences. Subregional quantification of the amygdala, particularly when combined with plasma pTau biomarkers, may provide sensitive early indicators of disease-related neurodegeneration, reflect network-level vulnerability, and improve understanding of cognitive decline, confirming its potential utility as a biomarker in AD research and clinical practice.