Fig. 2

Three hypotheses of hippocampal sparing AD based on different initiation and end sites of tau pathology. Based on initiation and end sites of tau pathology (a), we hypothesized three possible scenarios: (b) NFT accumulation follows the stereotypical order defined by Braak and Braak [10], where NFT in the hippocampus always precede NFT in the association cortex. Hence, hippocampal sparing AD would only exist in Braak stage V and VI and reflects individuals with NFT predominantly in the association cortex. The colors represent mild (yellow), moderate (orange), and severe (red) degrees of tau pathology. Colors in panel b are just hypothetical examples to represent that in the hippocampal sparing subtype, tau pathology would reach a higher degree of pathology in the cortex (e.g. in red, severe degree), than in the hippocampus (e.g. in yellow, mild degree). However, other degrees of pathology are possible. For example, typical AD is defined by balanced degrees of pathology in cortex and hippocampus, so that the degrees of pathology can indeed be mild, moderate, or severe, while in our Fig. 2b we depicted them in orange for illustration purposes); (c) NFT accumulation in the association cortex precedes NFT accumulation in the hippocampus, occurring before Braak stage II, but all subtypes converge at Braak stage V/VI. Again, colors in panel c are just hypothetical examples and other degrees of pathology are also possible; and (d) NFT accumulates in the association cortex while completely sparing the hippocampus across the entire disease progression up to death. As for the other two hypotheses, colors in panel d are just hypothetical examples and other degrees of pathology are also possible. Only the “distinct cortical” hypothesis would support the existence of a strictly hippocampal sparing subtype of AD, since the “cortical predominance” and “cortical precedence” hypotheses imply the presence of tau NFT in the hippocampus. Panels b, c, and d show examples of the hippocampal sparing AD subtype, and the depicted colors are just examples, but other degrees of pathology are also possible as long as the level of pathology in cortex is higher than that in hippocampus (which defines this subtype). The figure has a focus on hippocampal sparing AD, and it does not provide examples for other subtypes such as limbic predominant AD or minimal tau AD, in all the panels. Abbreviations: AD = Alzheimer’s disease; NFT = neurofibrillary tangles