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. 2015 Oct 13;85(15):1354–1355. doi: 10.1212/01.wnl.0000472918.79256.a9

The TMEM106B locus and TDP-43 pathology in older persons without FTLD

Dennis W Dickson 1, Rosa Rademakers 1, Alexandra M Nicholson 1
PMCID: PMC5990310  PMID: 26459943

Yu et al.1 investigated the association of TMEM106B variants with TAR-DNA binding protein 43 (TDP-43) pathology in elderly individuals without frontotemporal lobar degeneration (FTLD-TDP). They also examined whether these associations were independent of comorbid pathologic processes, such as Alzheimer disease (AD) and hippocampal sclerosis (HS). The results confirmed earlier findings that TMEM106B variants are an important TDP-43 pathology risk factor in FTLD-TDP, sporadic amyotrophic lateral sclerosis, AD, tangle predominant dementia, and Lewy body disease.24 The authors also reported a lack of association between TMEM106B variants and HS after adjusting for the presence of TDP-43 pathology. This likely reflects lack of specificity in the HS diagnostic criteria.

Evidence suggests that HS in the elderly is a degenerative process that can be distinguished from hippocampal neuronal loss associated with anoxic-ischemic injury or epilepsy by the presence of TDP-43 pathology.5 Grouping HS of the elderly with HS due to other etiologies confounds the results and weakens the TMEM106B association with HS of the elderly. Current evidence suggests the strongest genetic determinant of HS in the elderly is TMEM106B and more precise neuropathologic criteria for HS should be used when assessing genetic risk factors for HS.

Neurology. 2015 Oct 13;85(15):1354–1355.

Author Response

Julie A Schneider 1, Lei Yu 1, David A Bennett 1

We thank Dickson et al. for their comments on our article.1 They expressed concern that by including HS without TDP pathology in the definition of HS we may have masked an association of the TMEM variant with HS. In our study, 13% (n = 70) of 544 subjects had HS pathology. Of these, TDP was present in 60 (86%; HS+TDP) and absent in 10 (14%; HS-TDP). To address their concern, we excluded HS-TDP and revised our logistic regression model using HS+TDP as the outcome. We did not find a significant association of TMEM with HS+TDP (odds ratio 1.183, 95% confidence interval 0.799–1.752, p = 0.402).

To ensure results were not confounded by TDP, we repeated the model by further controlling for TDP and results were unchanged (p = 0.512). Overall, while we agree that HS with and without TDP may reflect differing disease processes, these analyses show that a relationship between TMEM and HS was not masked by our inclusive definition and support that TMEM is related specifically to the pathology of TDP. However, results might vary with larger numbers of HS cases, especially if one considers HS+TDP as the outcome. Further studies of the TMEM variant, HS, and TDP pathology in community-based cohorts are warranted.

References

  • 1.Yu L, De Jager PL, Yang J, et al. The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology 2015;84:927–934. [DOI] [PMC free article] [PubMed] [Google Scholar]
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