ORIGINAL PAPER 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 Yvonne S. Davidson • Samantha Raby • Penelope G. Foulds • Andrew Robinson • Jennifer C. Thompson • Stephen Sikkink • Imran Yusuf • Hanan Amin • Daniel DuPlessis • Claire Troakes • Safa Al-Sarraj • Carolyn Sloan • Margaret M. Esiri • Vee P. Prasher • David Allsop • David Neary • Stuart M. Pickering-Brown • Julie S. Snowden • David M. A. Mann Received: 8 August 2011 / Revised: 6 September 2011 / Accepted: 6 September 2011 Ó Springer-Verlag 2011 Abstract TDP-43 immunoreactive (TDP-43-ir) pathologi- cal 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 spo- radic 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 Electronic supplementary material The online version of this article (doi:10.1007/s00401-011-0879-y) contains supplementary material, which is available to authorized users. Y. S. Davidson Á A. Robinson Á J. C. Thompson Á I. Yusuf Á H. Amin Á D. DuPlessis Á D. M. A. Mann (&) 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 e-mail: david.mann@manchester.ac.uk S. Raby Á P. G. Foulds Á D. Allsop Division of Biomedical and Life Sciences, School of Health and Medicine, University of Lancaster, Lancaster LA1 4YQ, UK S. Sikkink Á S. M. Pickering-Brown Mental Health and Neurodegeneration Research Group, Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK C. Troakes Á S. Al-Sarraj London Neurodegenerative Diseases Brain Bank, Department of Clinical Neuroscience, Institute of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF, UK C. Sloan Á M. M. Esiri Neuropathology Department, John Radcliffe Infirmary, University of Oxford, Level 1 West Wing, Oxford OX3 9DU, UK V. P. Prasher South Birmingham Community NHS Trust, Birmingham, UK V. P. Prasher Liverpool John Moores University, Liverpool, UK J. C. Thompson Á D. Neary Á J. S. Snowden Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Hope Hospital, Stott Lane, Salford M6 8HD, UK 123 Acta Neuropathol DOI 10.1007/s00401-011-0879-y