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The MAPT H1 haplotype is associated with tangle-predominant dementia

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Abstract

Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aβ)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble Aβ in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated Aβ is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein α (sAPPα) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (MAPT). Haplotype analysis demonstrates a strong association between TPD and the MAPT H1 haplotype, a genomic inversion associated with some tauopathies and Parkinson disease (PD), when compared to age-matched control subjects with mild degenerative changes, i.e., successful cerebral aging. Next-generation resequencing of MAPT followed by association analysis shows an association between TPD and two polymorphisms in the MAPT 3′ untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the MAPT 3′ UTR underlies an Aβ-independent mechanism for neurodegeneration in TPD.

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Acknowledgments

We express our deepest gratitude to the patients and staff of the contributing centers and institutes, including the Taub Institute for Research on Alzheimer’s Disease & the Aging Brain at Columbia University [(P50AG08702/RO1AG037212), the Washington/Hamilton Heights-Inwood Columbia Aging Project (P01AG07232) and the Essential Tremor Centralized Brain Repository (R01NS042859)], the Sanders-Brown Center on Aging at the University of Kentucky (P30AG028383), the Shiley-Marcos Alzheimer’s Disease Research Center at the University of California San Diego (P50AG05131), the Northwestern University Alzheimer’s Disease Center (AG13854 and the NADC Neuropathology Core Tissue Bank), the Washington University School of Medicine, St. Louis, MO [NIA P50-AG05681, P01-AG03991), the Hope Center for Neurological Disorders, and the Charles F. & Joanne Knight Alzheimer’s Disease Research Center], the University of Washington Neuropathology Core [Alzheimer’s Disease Research Center (AG05136), the Adult Changes in Thought Study (AG006781), and Morris K Udall Center of Excellence for Parkinson’s Disease Research (NS062684)], and the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona [National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research]. We thank Drs. Michael L. Shelanski and Richard Mayeux. We also thank Drs. Jean-Paul Vonsattel and Lawrence Honig for providing the patients’ clinical and neuropathological data. We thank Dr. Etty Cortes for helpful comments and neuropathology core support. We thank Arlene Lawton for coordination of brain donations at Columbia University. We further thank Drs. Karen Duff and James E. Goldman for helpful comments. We thank Dr. Peter Davies for the phospho-tau antisera. Finally, we thank Kristy Brown for electron microscopy support. This project was funded in part by American Recovery and Reinvestment Act (ARRA) funds through Grant number P30AG036453 (MLS). This project was also supported by the Alzheimer’s Association (NIRG-11-204450) and the Louis V. Gerstner, Jr., Foundation (JFC).

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Authors and Affiliations

  1. Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, 10032, USA

    Ismael Santa-Maria, Aya Haggiagi, Xinmin Liu, Lorraine N. Clark & John F. Crary

  2. Department of Human Genetics, McGill University, Montreal, QC, H3A 1A4, Canada

    Jessica Wasserscheid & Ken Dewar

  3. Division of Neuropathology, Department of Pathology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone, Lexington, KY, 40536, USA

    Peter T. Nelson

  4. Department of Pathology and Cell Biology, Columbia University Medical Center, 630 168th Street PH15-124, New York, NY, 10032, USA

    John F. Crary

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  1. Ismael Santa-Maria
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Santa-Maria, I., Haggiagi, A., Liu, X. et al. The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathol 124, 693–704 (2012). https://doi.org/10.1007/s00401-012-1017-1

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