. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol. 2007 May;61(5):435-45. PubMed.

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  1. This paper by Amador-Ortiz et al. is an excellent and very thorough paper that adds TDP-43 pathologies to the lesions formed by misfolding proteins in AD. AD appears to be associated with TDP-43 proteinopathy almost as often as it is associated with alpha-synucleinopathy (~50 percent of cases of familial and sporadic AD have Lewy bodies and Lewy neurites). This presents an additional challenge to advocates of the Abeta cascade hypothesis, who now must explain how this hypothesis can account for why Lewy bodies as well as TDP-43 lesions occur often in AD. We and others are finding a similar co-ccurence of TDP-43 lesions in AD, albeit to a lesser extent. The initial paper by Neumann M., et al (Science, 2006) did not show this pathology in AD most likely due the small number of AD cases examined.

    However, Amador-Ortiz et al report a higher percentage of AD cases with TDP-43 lesions than we are seeing in the larger series of AD cases that we have examined more recently. This may reflect a bias in the AD cohort study by Amador-Ortiz et al. that might include a large number of AD subjects with concomitant FTLD-U. All of this will be sorted out very quickly, as the TDP-43 proteinopathy field is hot and there is incredible activity in this area that will rapidly clarify these and other aspects of TDP-43 proteinopathies in the coming year (see reviews that are part of a special cluster of related papers on TDP-43 to appear shortly in Acta Neuropathology).