Clinical validity of Aβ-protein deposition staging in brain aging and Alzheimer disease

Braak's neurofibrillary tangle (NFT) pathology staging system of Alzheimer disease (AD) correlates generally with clinical data. Recently, Braak's group proposed an Aβ-protein staging based on the progression of amyloid deposition in the medial temporal lobe. To examine its clinical validity and evaluate whether it adds predictive power to NFT-based staging, we performed a study comparing both neuropathological classifications with clinical dementia rating scale (CDR) scores in a large autopsy series. The 2 neuropathological staging systems were strongly correlated. Their association with clinical severity was highly significant. However, the strength of the relationship was greater for NFT-based staging. It accounted for 26.5% of the variability in clinical severity, Aβ-protein-based staging for 13.0%, and age for 4.4%. Compared to NFT-based staging, the Aβ-protein-based system was less able to distinguish mild cognitive changes from dementia and showed marked overlap among the various stages of cognitive decline. In a multivariate model, NFT and age together accounted for 27.2% of the clinical variability and the addition of Aβ-protein deposition staging could only explain an extra 2.9%. Our data support the close relationship between NFT progression and amyloid formation within the medial temporal lobe proposed by Braak's group but demonstrate the limited value of Aβ-protein deposition staging in terms of clinicopathological correlations.