Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degreeof dementia

Abnormal phosphorylation of the tau-protein is regarded as a crucial step i n the formation of neurofibrillary tangles in the neuronal cell body and ne uropil threads in dendrites. We studied the effects of tau-pathology on the clinical expression of dementia in 106 autopsy cases in the entorhinal reg ion, the hippocampal stratum oriens, the stratum radiatum, and the perforan t path target zone. The first cytoskeletal lesions were located in the peri karya and dendrites of the pre-alpha cells of the transentorhinal and entor hinal region. Next, abnormally phosphorylated tau-protein (PHF-tau) was fou nd in the neuropil of the CA1-subiculum region. Thereafter, the stratum rad iatum and stratum oriens began to be involved in PHF-tau pathology in Braak stage II. In the Braak stages TV and V, the stratum radiatum was completel y involved, the stratum oriens increasingly so. Beginning in Braak stage II I, we noted cases having PHF-tau pathology in the perforant path target zon e of the outer molecular layer of the dentate gyrus. The increase of this p athology with ever greater involvement on the part of the entorhino-hippoca mpal circuit correlated significantly not only with the Braak stages and wi th the neurochemically determined hippocampal content of PHF-tau but also w ith the degree of dementia as defined by the clinical dementia rating (CDR) scale. The affection of the stratum oriens in combination with PHF-tau pat hology in the stratum radiatum and in the outer molecular layer of the dent ate gyrus was encountered almost exclusively in demented individuals (CDR). These results indicate that axonal PHF-tau pathology in hippocampal pathwa ys presumably is critical for the clinical expression of dementia and may c onstitute an anatomical substrate of clinically verifiable memory dysfuncti on in Alzheimer's disease. (C) 2000 Academic Press.