Brainstem tau pathology in Alzheimer's disease is characterized by increase of three repeat tau and independent of amyloid ß.

INTRODUCTION: Alzheimer-type neuropil threads (NTs) and neurofibrillary tangles (NFTs) are comprised of either 4 repeat (4R)-tau, 3 repeat (3R)-tau, or a mixture of both. In the hippocampus, the number of NFTs, and the proportion of 3R tau progressively increases. If this preferential accumulation of 3R tau also occurs in the brainstem, it may be fundamentally related to progression of Alzheimer pathology. METHODS: Midbrain and pontine sections of brainstems from 23 cases (Braak-NFT stages I/II: 8, III/IV: 8, and V/VI: 7) were double immunofluorolabeled for 4R and 3R tau. High-resolution (0.645 µm/pixel), in-focus snapshots were tiled to cover entire brain sections using a virtual slide system. Each lesion was classified by size (NT < 200 µm2 < NFT) and staining profile (3R/4R). In addition, the localization and quantity of amyloid ß (Aß) deposits were examined in adjacent sections for comparison with tau. RESULTS: The data sets obtained from approximately 286 gigabytes of image files consisted of 847,763 NTs and 7859 NFTs. The proportion of 3R tau-positive NTs and NFTs in the midbrain, and 3R tau-positive NTs in the pons gradually increased with advancing NFT stages, while the proportion of 3R tau-positive NFTs in the pons was already elevated at early stages. Aß deposits were absent at NFT stages I/II, and when present at later stages, their regional distribution was different from that of tau. These observations suggest that a progressive increase in the proportion of 3R tau occurs independently of Aß deposits. CONCLUSIONS: This is the first quantitative analysis of NFTs and NTs in the human brainstem. We demonstrate that the proportion of 3R tau in the brainstem neurofibrillary changes increases with disease progression. Because this phenomenon is shared between the brainstem and the hippocampus, this increase may be fundamental to the pathogenesis of Alzheimer disease.