Lemere CA, Head E, Holtzman DM. APOE ε4 Association With Cognition and Alzheimer Disease Biomarkers in Down Syndrome-Implications for Clinical Trials and Treatments for All. JAMA Neurol. 2021 Aug 1;78(8):913-915. PubMed.

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  1. This important paper from the Fortea and Zaman groups further strengthens the notion that AD in DS shares many similar features to other forms of AD (i.e., sporadic and autosomal-dominant AD), including the increased risk associated with the APOE4 allele.

    The authors present data that were collected from a dual center study of adults with DS (n=464). They report that APOE4 carriers presented with AD symptoms at a younger age (50.7 vs. 52.7 years) and showed differences in standard AD biomarker trajectories (Aβ measures in CSF and PET and atrophy on MRI), similar to what is observed in other forms of AD. Interestingly, they did not find differences between APOE4 carriers and noncarriers with regard to NfL fluid biomarkers or CSF total tau or p-tau-181.

    The authors specifically report that the APOE4 allele was associated with age-associated changes in all three categories of the ATN framework (amyloid, tau, and neurodegeneration). The associations with amyloid pathology appeared to be the earliest (differences in the early 20s for CSF Aβ42-to-Aβ40 ratio and in the mid-30s for amyloid PET), the greatest, and the most consistent across the different biomarkers. In addition, they found lower levels of CSF Aβ42 and CSF Aβ42-to-Aβ40 ratio associated with the APOE4 allele. These finding reproduce previous observations in both sporadic AD and autosomal-dominant AD.

    The relationship between the APOE4 allele and AD risk was first made by Elizabeth Corder, Warren Strittmatter, and the late Allen Roses and their colleagues in a set of landmark studies (Corder et al., 1993; Strittmatter et al., 1993; Saunders et al, 1993). I vividly recall being in the audience at the SFN meeting in Washington, D.C., when the data was first presented. The scientific debate was intense yet inspiring, and contributed to my own interest in entering the field of AD research while an undergraduate student.

    The following year, it was demonstrated that the APOE2 allele was protective against AD (Corder et al., 1994). Since then, thousands of papers have been published on the relationship between AD and APOE, though there is still no consensus on a mechanistic explanation for this genetic association. It also remains to be confirmed if the APOE2 allele is also protective against AD in DS, although there has been some work indicating that this may indeed be the case (Royston et al, 1996). 

    This paper by Bejanin reinforces the idea that stratification based on APOE4 carrier status will be critical to consider when designing clinical trials for AD in DS. In addition, the impact of APOE4 on biological markers of AD offers potential new therapeutic targets for AD in persons with DS.

    References:

    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PubMed.

    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. PubMed.

    Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994 Jun;7(2):180-4. PubMed.

    Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994 Jun;7(2):180-4. PubMed.

    Royston MC, Mann D, Pickering-Brown S, Owen F, Perry R, Ragbavan R, Khin-Nu C, Tyner S, Day K, Crook R, Hardy J, Roberts GW. ApoE2 allele, Down's syndrome, and dementia. Ann N Y Acad Sci. 1996 Jan 17;777:255-9. PubMed.

    View all comments by Michael Rafii

  2. The findings here are in keeping with previous studies that have shown the effect of APOE E4 alleles in aging adults with Down’s syndrome, with an earlier onset of cognitive decline. The addition of biomarker data in this report confirm it may be associated with differences in early markers of the Alzheimer's disease pathological process.

    An intriguing finding from our work is that APOE E4 alleles may confer a cognitive advantage in early life, which is perhaps more pronounced in individuals with DS, who have a background of delayed development, in contrast to the earlier decline in later life (for details see D’Souza et al., 2020). 

    References:

    D'Souza H, Mason L, Mok KY, Startin CM, Hamburg S, Hithersay R, Baksh RA, Hardy J, Strydom A, Thomas MS, London Down Syndrome (LonDownS) Consortium. Differential Associations of Apolipoprotein E ε4 Genotype With Attentional Abilities Across the Life Span of Individuals With Down Syndrome. JAMA Netw Open. 2020 Sep 1;3(9):e2018221. PubMed.

    View all comments by Andre Strydom

  3. This excellent, definitive, and timely study, in a large sample of individuals with Down's syndrome, carefully examines if APOe4 effects are consistent with findings in non-DS populations. This work is highly important. It not only confirms the results of previous studies revealing an earlier age on dementia onset associated with e4 carriers—in addition to stratifying prevalence based on age—but also informs us on differences in AD-related biomarkers between carriers and noncarriers. This information on neuroimaging and fluid biomarkers is critical for characterizing the AT(N) framework in DS and for the design and conduct of clinical intervention trials

    View all comments by Bradley T. Christian

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  1. ApoE4 Hastens Alzheimer’s Disease in Down’s Syndrome