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July 17, 2014
TDP-43 and Alzheimer's
There are quite a few headlines today about a link between Alzheimer's and a protein called TDP-43. This is interesting stuff, but like everything else in the neurodegeneration field, it's going to be tough to unravel what's going on. This latest work, just presented at a conference in Copenhagen, found (in a large post mortem brain study of people with diagnosed Alzheimer's pathology) that aberrant forms of the protein seem to be strongly correlated with shrinkage of the hippocampus and accompanying memory loss.
80% of the cohort with normal TDP-43 (but still showing Alzheimer's histology) had cognitive impairment at death, but 98% of the ones with TDP-43 mutations had such signs. That says several things: (A) it's possible to have classic Alzheimer's without mutated TDP-43, (B) it's possible to have classic Alzheimer's tissue pathology (up to a point, no doubt) without apparent cognitive impairment, and (C) it's apparently possible (although very unlikely) to have mutated TDP-43, show Alzheimer's pathology as well, and still not be diagnosed as cognitively impaired. Welcome to neurodegeneration. Correlations and trends are mostly what you get in that field, and you have to make of them what you can.
TDP-43, though, has already been implicated, for some years now, in ALS and several other syndromes, so it really does make sense that it would be involved. It may be that it's disproportionately a feature of more severe Alzheimer's cases, piling on to some other pathology. Its mechanism of action is not clear yet - as mentioned, it's a transcription factor, so it could be involved in stuff from anywhere and everywhere. It does show aggregation in the disease state, but that Cell paper linked to above makes the case that it's not the aggregates per se that are the problem, but the loss of function behind them (for example, there are increased amounts of the mutant protein out in the cytoplasm, rather than in the nucleus). What those lost functions are, though, remains to be discovered.
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