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TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s Syndrome: association with age, hippocampal sclerosis and clinical phenotype

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Abstract

TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer’s disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down’s Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.

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Acknowledgments

We thank Helen Morpeth in Pathological Services at Salford Royal Foundation Trust for technical assistance. We acknowledge the assistance of Professor Martin Rossor at Institute of Neurology, Queen Square, London in the collection and characterisation of some of the familial Alzheimer’s disease cases. The work of the Manchester Brain Bank, the Thomas Willis Brain Bank, Oxford, and the Institute of Psychiatry Brain Bank is supported by wholly or in part by Alzheimer’s Research UK and the Alzheimer’s Society through the Brains for Dementia Research Initiative. SR is supported by The Sir John Fisher Foundation. MME is grateful for support from the UK National Institute for Health Research via the Biomedical Research Centre.

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Authors and Affiliations

  1. Mental Health and Neurodegeneration Research Group, Faculty of Medical and Human Sciences, Salford Royal Foundation Trust, University of Manchester, Stott Lane, Salford, M6 8HD, UK

    Yvonne S. Davidson, Andrew Robinson, Jennifer C. Thompson, Imran Yusuf, Hanan Amin, Daniel DuPlessis & David M. A. Mann

  2. Division of Biomedical and Life Sciences, School of Health and Medicine, University of Lancaster, Lancaster, LA1 4YQ, UK

    Samantha Raby, Penelope G. Foulds & David Allsop

  3. Mental Health and Neurodegeneration Research Group, Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK

    Stephen Sikkink & Stuart M. Pickering-Brown

  4. London Neurodegenerative Diseases Brain Bank, Department of Clinical Neuroscience, Institute of Psychiatry, King’s College London, De Crespigny Park, London, SE5 8AF, UK

    Claire Troakes & Safa Al-Sarraj

  5. Neuropathology Department, John Radcliffe Infirmary, University of Oxford, Level 1 West Wing, Oxford, OX3 9DU, UK

    Carolyn Sloan & Margaret M. Esiri

  6. South Birmingham Community NHS Trust, Birmingham, UK

    Vee P. Prasher

  7. Liverpool John Moores University, Liverpool, UK

    Vee P. Prasher

  8. Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Hope Hospital, Stott Lane, Salford, M6 8HD, UK

    Jennifer C. Thompson, David Neary & Julie S. Snowden

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  1. Yvonne S. Davidson
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Correspondence to David M. A. Mann.

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Davidson, Y.S., Raby, S., Foulds, P.G. et al. TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s Syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol 122, 703–713 (2011). https://doi.org/10.1007/s00401-011-0879-y

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