Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation

  • Cathrine Petersen
  • Amber L. Nolan
  • Elisa de Paula França Resende
  • Zachary Miller
  • Alexander J. Ehrenberg
  • Maria Luisa Gorno-Tempini
  • Howard J. Rosen
  • Joel H. Kramer
  • Salvatore Spina
  • Gil D. Rabinovici
  • Bruce L. Miller
  • William W. Seeley
  • Helmut Heinsen
  • Lea Tenenholz GrinbergEmail author
Original Paper


The clinical spectrum of Alzheimer’s disease (AD) extends well beyond the classic amnestic–predominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (p = 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (p = 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with worsening visuospatial dysfunction. In addition, unbiased hierarchical clustering based on regional NFT densities identified three groups characterized by a low overall NFT burden, high overall burden, and cortical-predominant burden, respectively, which were found to differ in sex ratio, age, disease duration, and clinical presentation. In comparison, the typical, hippocampal sparing, and limbic-predominant subtypes derived from a previously proposed algorithm did not reproduce the same degree of clinical relevance in this sample. Overall, our results suggest domain-specific functional consequences of regional NFT accumulation. Mapping these consequences presents an opportunity to increase understanding of the neuropathological framework underlying atypical clinical manifestations.


Alzheimer’s disease Neurofibrillary tangles Atypical Alzheimer’s disease Tau pathology Autopsy Human 



The authors thank the patients and their families for their invaluable contribution to brain aging neurodegenerative disease research. ER is an Atlantic Fellow for Equity in Brain Health and thanks the fellowship for supporting her work. This study was supported by the National Institute of Health Grant K24AG053435 and institutional Grants P50AG023501, P01AG019724. MLGT was funded by the National Institute of Health Grants K24DC015544A and R01NS50915.

Compliance with ethical standards

Conflict of interest

The authors have no duality or conflicts of interest to declare.

Ethical approval

This study was approved by the UCSF Institutional Review Board (reference number) and all the participants or their legal representatives signed a written informed consent that was obtained according to the 1964 Declaration of Helsinki and its further amendments.

Data availability

The data sets used and analyzed during the current study are available from the corresponding author upon reasonable request. Raw data are provided as supplementary material.

Supplementary material

401_2019_2036_MOESM1_ESM.pdf (1.7 mb)
Supplementary material 1 (PDF 1709 kb)
401_2019_2036_MOESM2_ESM.pdf (149 kb)
Supplementary material 2 (PDF 148 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Cathrine Petersen
    • 1
  • Amber L. Nolan
    • 1
  • Elisa de Paula França Resende
    • 1
    • 2
  • Zachary Miller
    • 1
  • Alexander J. Ehrenberg
    • 1
  • Maria Luisa Gorno-Tempini
    • 1
  • Howard J. Rosen
    • 1
  • Joel H. Kramer
    • 1
  • Salvatore Spina
    • 1
  • Gil D. Rabinovici
    • 1
  • Bruce L. Miller
    • 1
  • William W. Seeley
    • 1
  • Helmut Heinsen
    • 3
    • 4
  • Lea Tenenholz Grinberg
    • 1
    • 2
    • 5
    • 6
    Email author
  1. 1.Memory and Aging Center, Weill Institute for Neurosciences, University of CaliforniaSan FranciscoUSA
  2. 2.Global Brain Health Institute Based at University of California, San Francisco and Trinity CollegeDublinIreland
  3. 3.LIM-44University of Sao Paulo Medical SchoolSao PauloBrazil
  4. 4.Clinic of PsychiatryUniversity of WürzburgWurzburgGermany
  5. 5.LIM-22, Department of PathologyUniversity of Sao Paulo Medical SchoolSao PauloBrazil
  6. 6.Departments of Neurology and PathologyUCSFSan FranciscoUSA

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