Sequence of Aβ-Protein Deposition in the Human Medial Temporal Lobe

The deposition of Aβ-protein (Aβ) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Aβ-deposits occurring in the course of AD, as well as for the relationship between the development of Aβ-deposition and that of neurofibrillary pathology. In the first of 4 phases of β-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-β and pre-γ, and fleecy amyloid deposits occur in the internal entorhinal layers pri-α, pri-β, pri-γ, and in CA1. In the third phase, Aβ-deposits emerge in the molecular layer of the fascia dentata, and band-like Aβ-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Aβ-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-α. Parallel to the evolution of β-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Aβ and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Aβ-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of β-amyloidosis. The 4 phases in the evolution of β-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.