The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old

Neurofibrillary pathology as found in Alzheimer's disease (AD) is also foun d in the normal elderly, suggesting that these changes may be part of the a ging process. In this study, we assessed the densities and distribution of structures recognized by the monoclonal antibody (mAb) to phosphorylated ta u (AT8) in the hippocampal formation and medial temporal isocortex of 19 ce ntenarians. Of these, 4 cases were demented and 15 non-demented. AT8 immuno reactivity correlated with the global deterioration scale (GDS). The densit y of both intraneuronal neurofibrillary tangles (I-NFTs) and neuritic clust ers (NCs) significantly correlated with the GDS in the layer II of the ento rhinal cortex (r = 0.66, P = 0.005 and r = 0.611, P = 0.01, respectively). Density of I-NFTs in the subiculum (r = 0.491; P = 0.034) also correlated s ignificantly. No other area was found to be statistically significant. Impo rtantly, no correlation was found when demented and non-demented centenaria n cases were analyzed separately, suggesting that the difference marks a fu ndamental shift between AD and non-demented individuals. This assertion is supported by the significantly higher densities of I-NFTs and NCs in the tr ansentorhinal (P = 0.043 and P = 0.011, respectively) and layer II of the e ntorhinal cortex (P = 0.02 and P = 0.007, respectively), and I-NFTs in the subiculum (P < 0.001) and CA1 (P = 0.011) in the demented group when compar ed with the non-demented cases. Granular diffuse deposits, an early stage p arameter of the neurofibrillary pathology involving accumulation of non-fib rillar abnormally phosphorylated tau protein did not correlate with the GDS or between the two groups studied. This study, combining morphometric and confocal analyses, not only provides further evidence that, in the brains o f patients with AD, the perforant pathway is highly sensitive to tau pathol ogy but also that involvement is distinct from the changes of normal aging, even of the oldest old.