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Neuropathologically defined subtypes of Alzheimer’s disease differ significantly from neurofibrillary tangle-predominant dementia

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Abstract

Alzheimer’s disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (n = 18) with LP AD (n = 19), as well as the other AD subtypes, typical AD (n = 52) and HpSp AD (n = 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD. MAPT H1H1 genotype frequency was high (~70 %) in NFTD and LP AD, and similar to typical AD, while APOE ε4 carrier state was low in NFTD. While it shares clinical similarities with regard to female sex predominance, onset in advanced age, and a slow cognitive decline, NFTD has significant pathologic differences from LP AD, suggesting that it may not merely be a variant of AD.

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Acknowledgments

The project was supported by the Mayo ADRC Grant (P50 AG16574), Mayo Clinic Study on Aging (U01 AG06786), Florida ADRC (P50 AG215711), Einstein Aging Study (P01 AG03949), Mangurian Foundation, and the State of Florida Alzheimer’s Disease Initiative. MEM and this project were supported by a fellowship from the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program and the Mayo ADRC Pilot Grant. OAR and DWD were supported by the Mayo Clinic Udall Center (P50 NS072187). OAR was partially supported by R01 NS078086. DWD was supported by the Robert E Jacoby Professorship for Alzheimer’s Research. We thank the patients and their families who donated brains to help further our knowledge in neurodegeneration. The authors would like to acknowledge the endless hours of commitment and teamwork offered by Linda G. Rousseau, Virginia R. Phillips, John Gonzalez, and Monica Castanedes-Casey. Without the sampling design and procedures for thioflavin-S fluorescent microscopy developed originally by Dr. Robert D. Terry [36], this study would not have been possible.

Ethical approval

All research reported is on postmortem material, which is considered exempt from human subject research. All brains were acquired with appropriate ethical approval and the research described has approval from the Mayo Clinic Institutional Review Board.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Nicholas J. Janocko, Kevin A. Brodersen, Alexandra I. Soto-Ortolaza, Owen A. Ross, Amanda M. Liesinger, Dennis W. Dickson & Melissa E. Murray

  2. Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, USA

    Ranjan Duara

  3. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Neill R. Graff-Radford

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  1. Nicholas J. Janocko
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Correspondence to Melissa E. Murray.

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Janocko, N.J., Brodersen, K.A., Soto-Ortolaza, A.I. et al. Neuropathologically defined subtypes of Alzheimer’s disease differ significantly from neurofibrillary tangle-predominant dementia. Acta Neuropathol 124, 681–692 (2012). https://doi.org/10.1007/s00401-012-1044-y

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