The histopathological staging of tau, but not amyloid, corresponds to antemortem cognitive status, dementia stage, functional abilities and neuropsychiatric symptoms

Abstract

Purpose Alzheimer’s disease (AD) is characterised by two cardinal pathologies, namely the extracellular accumulation amyloid-related aggregates, and the intracellular formation of tau-related neurofibrillary tangles (NFTs). While both pathologies disrupt cognitive function, a large body of evidence suggests that tau-pathology has a stronger relationship with the clinical manifestation of the disease compared to amyloid. Given the ordinal nature of histopathological staging systems, however, it is possible that the effect of amyloid pathology has been underestimated in clinicopathological studies. Methods We investigated this possibility using data from the National Alzheimer’s Coordinating Center (NACC) database, which contains data from patients in the United States of America. Bayesian ordinal models were used to directly investigate the relative contribution of Braak NFT, diffuse plaque, and neuritic plaque staging to the severity of antemortem clinical impairment. Results Data from 144 participants were included in the final analysis. Bayesian ordinal models revealed that Braak NFT stage was the only predictor of global cognitive status, clinical dementia stage, functional abilities, and neuropsychiatric symptoms. When compared directly, Braak NFT stage was a stronger predictor than diffuse or neuritic plaques across these domains. Conclusions These findings confirm that tau-related pathology is more strongly related to clinical status than amyloid pathology. This suggests that conventional clinical markers of disease progression might be insensitive to amyloid-pathology, and hence might be inappropriate for use as outcome measures in therapeutic trials that directly target amyloid.