Alzheimer-Related τ-Pathology in the Perforant Path Target Zone and in the Hippocampal Stratum Oriens and Radiatum Correlates with Onset and Degree of Dementia

Abstract

Abnormal phosphorylation of the τ-protein is regarded as a crucial step in the formation of neurofibrillary tangles in the neuronal cell body and neuropil threads in dendrites. We studied the effects of τ-pathology on the clinical expression of dementia in 106 autopsy cases in the entorhinal region, the hippocampal stratum oriens, the stratum radiatum, and the perforant path target zone. The first cytoskeletal lesions were located in the perikarya and dendrites of the pre-α cells of the transentorhinal and entorhinal region. Next, abnormally phosphorylated τ-protein (PHF-τ) was found in the neuropil of the CA1-subiculum region. Thereafter, the stratum radiatum and stratum oriens began to be involved in PHF-τ pathology in Braak stage II. In the Braak stages IV and V, the stratum radiatum was completely involved, the stratum oriens increasingly so. Beginning in Braak stage III, we noted cases having PHF-τ pathology in the perforant path target zone of the outer molecular layer of the dentate gyrus. The increase of this pathology with ever greater involvement on the part of the entorhinohippocampal circuit correlated significantly not only with the Braak stages and with the neurochemically determined hippocampal content of PHF-τ but also with the degree of dementia as defined by the clinical dementia rating (CDR) scale. The affection of the stratum oriens in combination with PHF-τ pathology in the stratum radiatum and in the outer molecular layer of the dentate gyrus was encountered almost exclusively in demented individuals (CDR 1–3). These results indicate that axonal PHF-τ pathology in hippocampal pathways presumably is critical for the clinical expression of dementia and may constitute an anatomical substrate of clinically verifiable memory dysfunction in Alzheimer's disease.