Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer's disease.

Duong, Michael Tran; Das, Sandhitsu R; Lyu, Xueying; Xie, Long; Richardson, Hayley; Xie, Sharon X; Yushkevich, Paul A; Alzheimer’s Disease Neuroimaging Initiative (ADNI) et al. · Nat Commun · 2022

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Abstract

Alzheimer's disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in <sup>18</sup>F-flortaucipir vs. <sup>18</sup>F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (N<sub>M</sub>) in 289 symptomatic patients from the Alzheimer's Disease Neuroimaging Initiative. We identified six T/N<sub>M</sub> clusters with differing limbic and cortical patterns. The canonical group was defined as the T/N<sub>M</sub> pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/N<sub>M</sub> mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.

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