The ApoE2 allele may increase the risk for dementia in people with amyotrophic lateral sclerosis. Yes, you read correctly—the authors of a paper in the February 22 JAMA Neurology online conclude that the same allele that is known to protect against Alzheimer’s disease more than doubles the chances that someone who has ALS will also have frontotemporal dementia. The study should be repeated to confirm this correlation, cautioned senior author Adriano Chiò of the University of Turin in Italy.

Many people with motor neuron disease also have symptoms of FTD, and vice versa. Scientists had already determined that genetic variants, in the form of hexanucleotide expansions in the C9ORF72 gene, make it more likely that a person with ALS will also develop FTD (Byrne et al., 2012). As for ApoE2, it had been linked previously to ALS and, separately, to FTD. ApoE2 was reported to delay the onset of ALS by about three years, though not to diminish chances of eventually getting the disease (Li et al., 2004). In the case of FTD, one study hinted that ApoE2 might boost risk, while more recent work pointed to an association between ApoE4, not ApoE2, and FTD (Verpillat et al., 2002; Rubino et al., 2013Ji et al., 2013).

These FTD studies were small, analyzing fewer than 200 people, and none tested for genetic association with incident dementia within ALS patients. Chiò examined the potential influence of ApoE on the presence of FTD among 357 people with ALS in the Piemonte and Valle de’Acosta regions of Italy. His registry enrolls nearly all people diagnosed with ALS in the area, finding them when they are referred by their neurologists or caretakers at other facilities, or in archives of reasons for hospital discharge or death (Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, 2001; Chiò et al., 2009). All of these participants, diagnosed between 2009 and 2013, had given DNA samples and underwent cognitive testing at the time of diagnosis. Fifty-one were identified as having ALS-FTD.

To his surprise, Chiò found that the ApoE2 allele appeared to correlate with FTD, increasing risk for coincident dementia by 2.61-fold. That is weaker than the effects of the C9ORF72 expansion, which in the same cohort raised chances of FTD 13.08-fold. By comparison, in the general population, carrying one copy of the ApoE4 allele increases the odds of Alzheimer’s by a factor of 3.68 (see AlzGene). Two copies of ApoE2 might further heighten FTD risk, Chiò speculated, but with only two homozygotes in his study cohort, he could not test this. Even having two homozygotes in a group of this size was a surprise, he said, given that ApoE2 is less frequent than ApoE4.

“I think it is too early to say whether ApoE2 is truly a risk factor for FTD in ALS,” commented Adam Boxer of the University of California in San Francisco. Likewise, G. William Rebeck of Georgetown University in Washington, D.C., praised the analysis but was unconvinced that ApoE2 affects dementia risk in ALS. Rebeck pointed out that of 38 ApoE2 carriers in the cohort, only eight developed FTD. One FTD case fewer and the association would not have been statistically significant, he noted.

However, disease risks from ApoE2 are not unheard of. The allele has been associated with risk for post-traumatic stress disorder, macular degeneration, and cerebral amyloid angiopathy (Johnson et al., 2015Schmidt et al., 2000; Nicoll et al., 1996). 

If the link between ApoE2 and ALS-FTD were shown to be true, then how might ApoE2 push the frontotemporal lobe toward degeneration? Chiò and Rebeck both suspect cholesterol metabolism. ApoE forms lipoproteins that package and shuttle cholesterol and other fats between cells. The ApoE2 protein binds less well to cell surface receptors than ApoE3 or E4, which compromises the lipid metabolism (Innerarity et al., 1984). Perhaps, Rebeck speculated, damaged neurons might be unable to get the lipids they need to recover.

Indeed, there is some evidence that lipid metabolism may be altered in people with ALS, though there is no consensus on how. According to one study, people with ALS who have high blood cholesterol live longer (Dupuis et al., 2008). In another, people with ALS who had trouble breathing tended to have lower serum cholesterol than those with better respiration (Chiò et al., 2009).

“I think this is a very interesting finding highlighting that genetic impacts on cognitive phenotypes of ALS might not be limited to C9ORF72,” commented Michael Hornberger of the University of East Anglia in Norwich, U.K., who did not participate in the study. Hornberger said brain imaging of people with ALS might offer clues to how ApoE2 makes things worse. One previous study of neurologically healthy people showed higher structural integrity of white matter in ApoE2 than ApoE3 carriers (Chiang et al., 2012). Chiò told Alzforum that many people in the Piemonte cohort have undergone PET scans, and he plans to analyze those data.—Amber Dance


  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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Paper Citations

  1. . Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012 Mar;11(3):232-40. PubMed.
  2. . Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis. Neurogenetics. 2004 Dec;5(4):209-13. PubMed.
  3. . Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis. Eur J Hum Genet. 2002 Jul;10(7):399-405. PubMed.
  4. . Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: A meta-analysis. Alzheimers Dement. 2013 May 17; PubMed.
  5. . Apolipoprotein Ε ε4 Frequency Is Increased among Chinese Patients with Frontotemporal Dementia and Alzheimer's Disease. Dement Geriatr Cogn Disord. 2013;36(3-4):163-70. PubMed.
  6. . Incidence of ALS in Italy: evidence for a uniform frequency in Western countries. Neurology. 2001 Jan 23;56(2):239-44. PubMed.
  7. . Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology. 2009 Feb 24;72(8):725-31. PubMed.
  8. . ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations. Neuropsychopharmacology. 2015 Sep;40(10):2443-53. Epub 2015 May 10 PubMed.
  9. . Association of the apolipoprotein E gene with age-related macular degeneration: possible effect modification by family history, age, and gender. Mol Vis. 2000 Dec 31;6:287-93. PubMed.
  10. . High frequency of apolipoprotein E epsilon 2 in patients with cerebral hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1996 May;39(5):682-3. PubMed.
  11. . Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation. J Biol Chem. 1984 Jun 10;259(11):7261-7. PubMed.
  12. . Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology. 2008 Mar 25;70(13):1004-9. PubMed.
  13. . Lower serum lipid levels are related to respiratory impairment in patients with ALS. Neurology. 2009 Nov 17;73(20):1681-5. PubMed.

Other Citations

  1. Chiang et al., 2012

External Citations

  1. AlzGene

Further Reading


  1. . Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012 Mar;135(Pt 3):784-93. PubMed.
  2. . APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann Neurol. 2015 Jun;77(6):917-29. PubMed.
  3. . Grey and white matter changes across the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS One. 2012;7(8):e43993. PubMed.
  4. . 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.
  5. . Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis. Neurogenetics. 1998 Mar;1(3):213-6. PubMed.

Primary Papers

  1. . The Role of APOE in the Occurrence of Frontotemporal Dementia in Amyotrophic Lateral Sclerosis. JAMA Neurol. 2016 Apr;73(4):425-30. PubMed.
  2. . To Dement or Not to Dement, That Is the Question. JAMA Neurol. 2016 Feb 22; PubMed.