Abnormally phosphorylated tau protein is found in the neuropil of the CA1-subiculum region, followed by the stratum radiatum and stratum oriens, correlating with Braak stage II. In the Braak stages IV and V, the stratum radiatum is fully affected, and the stratum oriens is increasingly affected. Beginning in Braak stage III, tau pathology is prominent in the perforant pathway target zone of the outer molecular layer of the dentate gyrus. Parahippocampal regions and limbic structures, early involved in the course of the disease, have olfactory connections. The primary olfactory cortical targets of the olfactory bulb, the piriform cortex and lateral entorhinal cortex project to the DG, CA3 and CA1 of the hippocampal formation (Lynch et al., 1991). Tau pathology in the olfactory bulb correlates with stage of disease (Attems and Jellinger, 2006) and volume of olfactory bulb and tract inversely correlates with global cognitive performance as determined by the mini-mental state examination [MMSE, (Thomann et al., 2009a; Thomann et al., 2009b)]. Likewise, impaired odor identification correlates with tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites (Wilson et al., 2007).
