Abstract Previous research has emphasized the unique impact of Alzheimer’s Disease (AD) pathology on the medial temporal lobe (MTL), a reflection that tau pathology is particularly striking in the entorhinal and transentorhinal cortex (ERC, TEC) early in the course of disease. However, other brain regions are affected by AD pathology during its early phases. Here, we use longitudinal diffeomorphometry to measure the atrophy rate from MRI of the amygdala compared with that in the ERC and TEC in controls, individuals who progressed from normal cognition to mild cognitive impairment (MCI), and individuals with MCI who progressed to AD dementia, using a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Our results show significantly higher atrophy rates of the amygdala in both preclinical and MCI ‘converters’ compared to controls, with rates of volume loss comparable to rates of thickness loss in the ERC and TEC. Using our recently developed method, referred to as Projective LDDMM, we map measures of neurofibrillary tau tangles (NFTs) from digital pathology to MRI atlases and reconstruct, for the first time, dense 3D spatial distributions of NFT density within regions of the MTL. The distribution of NFTs is consistent with the MR atrophy rates, revealing high densities not only in ERC, but in the amygdala and rostral third of the MTL. The similarity of the location of NFTs and shape changes in a well-defined clinical population suggests that amygdalar atrophy rate, as measured through MRI may be a viable biomarker for AD. PACS 0000, 1111 2000 MSC 0000, 1111 Highlights Amygdala atrophy rate estimated from MRIs in preclinical Alzheimer’s disease (AD) 3D distributions of neurofibrillary tau tangles (NFTs) reconstructed from 2D histology NFTs highest in the rostral medial temporal lobe, including amygdala and ERC Amygdala atrophy rate is comparable to ERC atrophy rate in preclinical AD Amygdala and ERC atrophy rates as potential biomarkers rooted in NFT pathology

Amygdalar and ERC Rostral Atrophy and Tau Pathology Reconstruction in Preclinical Alzheimer’s Disease