Yang HS, White CC, Klein HU, Yu L, Gaiteri C, Ma Y, Felsky D, Mostafavi S, Petyuk VA, Sperling RA, Ertekin-Taner N, Schneider JA, Bennett DA, De Jager PL. Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology. Neuron. 2020 Aug 5;107(3):496-508.e6. Epub 2020 Jun 10 PubMed.

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  1. TMEM106B has a strong association with brain pathology and was discovered as a risk allele in diseases on the ALS/FTLD spectrum. But indeed, the main impact of TDP-43 proteinopathy on public health is on LATE, which is >100-fold more common than ALS/FTLD conditions (~1:3 lifetime risk versus <1:1000 lifetime risk). It’s interesting that the rare variant of TMEM106B is actually protective.

    This new contribution by Yang and colleagues and the Rush University group is significant, and focused on LATE. This paper shows evidence of pathways that both TMEM106B and APOE contribute to, and there has been published evidence (including from Rush) that both TMEM106B and APOE status are associated with risk for TDP-43 proteinopathy in advanced age. One question that I had was whether or not other pathways associated with LATE show signals. GRN is only mentioned somewhat tangentially, whereas ABCC9 and KCNMB2 are not discussed.

    View all comments by Peter Nelson

  2. Thank you for your comment, Pete. Hopefully we as a field will learn a lot more about LATE in the coming years and get closer to identifying potential therapeutic targets.

    To answer your question, neither ABCC9 nor KCNMB2 variant showed a significant (p&lt;1.1x10^-9) or suggestive (p&lt;5x10^-8) module-QTL association in our study. I suspect that ABCC9 and KCNMB2 might act through different pathways than those we studied in this paper, and I think a more focused functional study of these two important genes would bring us additional insights.

    View all comments by Hyun-Sik Yang

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  1. TMEM106B Variants Regulate Gene Modules, TDP-43 Pathology