Tau‐neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer's continuum

Abstract

AbstractINTRODUCTIONVariability in relationship of tau‐based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non‐specific nature of N, modulated by non‐AD co‐pathologies, age‐related changes, and resilience factors.METHODSWe used regional T‐N residual patterns to partition 184 patients within the Alzheimer's continuum into data‐driven groups. These were compared with groups from 159 non‐AD (amyloid “negative”) patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T‐N residual model to classify 71 patients in an independent cohort into predefined groups.RESULTSAD groups displayed spatial T‐N mismatch patterns resembling neurodegeneration patterns in non‐AD groups, similarly associated with non‐AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T‐N mismatch correlated with TDP‐43 co‐pathology.DISCUSSIONT‐N mismatch may provide a personalized approach for determining non‐AD factors associated with resilience/vulnerability in AD.