Background: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta deposits and tau tangles, starting in cognitively normal (CN) adults, and leading to progressive cognitive impairment and dementia. In AD, tauopathy starts in the mesio-temporal lobe, including the amygdala-hippocampal complex. These anatomical structures are respectively composed of subnuclei and subfields that until recently could not be distinguished in-vivo. This possibility was recently implemented in FreeSurfer 7. We aimed to investigate the relative atrophy of the hippocampus and amygdala subregions in preclinical AD, specifically to evaluate whether the atrophy of specific subregions could inform about early tauopathy before cognitive impairment is noticeable. Methods: We first conducted an exploratory study in the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3) cohort including 144 amyloid-positive (A+) CN adults for which 3DT1-MRI and 18FAV1451 Tau-PET data were available. MRI data were processed in FreeSurfer 7. We identified hippocampal and amygdala sub-regions whose volume explained at least 1% of the variance in temporal tauopathy (meta-ROI). These regions were pooled to form two aggregates of tau-associated hippocampal (HA) and amygdala (AA) sub-structures. We subsequently validated these results in an independent cohort of 112 non-demented subjects from UCLouvain in which 3DT1-MRI and 18FMK-6240 Tau-PET were available. We evaluated the volume differences in previously defined sub-structure aggregates and in global structures. Individuals were either grouped based on their visual Braak-stage on Tau-PET or on a bioclinical classification (cognition (CN/MCI), amyloid (A-/A+) and tau (T-/T+)). Results: We first observed in the ADNI3 cohort that neither the global amygdala, nor hippocampal volume were associated with temporal tauopathy in the A+CN group (R2III or in A+T+MCI subjects. Conclusion: We identified a set of amygdala subnuclei whose atrophy is earlier than the atrophy of the global amygdala or hippocampus. The atrophy of these specific amygdala subnuclei is associated with temporal tauopathy in preclinical AD individuals, it distinguishes A+T+CN subjects from A-T-CN subjects, and visual Braak I-II from Braak 0 subjects. Measuring amygdala subnuclei volumes in older adults is thus a promising approach to identify individuals at-risk of progression to clinical AD.
Salman et al. (Mon,) studied this question.