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The CA2 sector of the hippocampus is relatively resistant to neurofibrillary tangles in aging and Alzheimer disease; however, some cases have selective neurofibrillary degeneration in CA2 with sparing of the more vulnerable CA1 sector. Cases such as this do not fit in the Braak and Braak staging scheme and can be considered to have an atypical pattern of neurofibrillary degeneration. We identified 24 atypical cases with an average age at death of 78.6 +/- 1.4 yr and average Braak stage of 3.2 +/- 0.4 and describe their pathologic and genetic characteristics with Gallyas silver staining, immunohistochemistry for tau and alphaB-crystallin, as well as apolipoprotein-E (ApoE) and tau genotyping. Three cases were excluded from further analysis due to presence of hippocampal sclerosis. All but 1 of the remaining 21 atypical cases were four-repeat (4R) tauopathies, including progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease (AGD). Remarkably, 19 of the 21 atypical cases were pure or mixed cases of AGD. The ApoE epsilon4 allele frequency was similar to normal controls, while there was a trend for an increased frequency of the extended tau H1 haplotype in atypical cases. Selective neurofibrillary degeneration in CA2 sector of the hippocampus is not widely recognized, but when detected should suggest the possibility of a 4R-tauopathy, particularly AGD.

Selective Neurofibrillary Degeneration of the Hippocampal CA2 Sector Is Associated with Four-Repeat Tauopathies