. To Dement or Not to Dement, That Is the Question. JAMA Neurol. 2016 Feb 22; PubMed.


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  1. Overall, I think this is a very interesting finding highlighting that genetic impacts on cognitive phenotypes of ALS might not be limited to C9ORF72. However, it would be important to replicate these findings, in particular as APOE2 genotypes have such low prevalence. Another important issue to investigate in the future is whether the APOE2 genotype impacts on the disease progression or survival of ALS patients. Another study of ours showed that cognitive or behavioral problems in ALS do not impact disease progression, whereas ALS-FTD patients progress much faster (Mioshi et al., 2014). This has clear implications for the patients and their families, as well as the clinical management of the patients.

    In terms of imaging, such as voxel-based morphology or diffusion tensor imaging, we have not correlated APOE genotypes with associated grey- or white-matter changes in ALS. However, based on this study, it clearly should be the next step.

    In general, there are very few APOE2 imaging studies conducted, likely due to the low prevalence of this allele and lesser importance for AD-related pathophysiology. Still, there is, for example, a study from Michael Weiner’s lab showing that APOE2 carriers have higher white-matter integrity than APOE3 carriers in posterior cingulate and corpus callosum white matter (Chiang et al., 2012). However, it is not clear how these changes might impact on the development of cognitive or full-blown FTD in ALS. Future studies in this direction would be important.


    . Neuropsychiatric changes precede classic motor symptoms in ALS and do not affect survival. Neurology. 2014 Jan 14;82(2):149-55. Epub 2013 Dec 11 PubMed.

    . White matter alterations in cognitively normal apoE ε2 carriers: insight into Alzheimer resistance?. AJNR Am J Neuroradiol. 2012 Aug;33(7):1392-7. Epub 2012 Mar 1 PubMed.

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  1. Et Tu, ApoE2? Paper Claims Allele Boosts Risk for Dementia—in ALS