Boon BD, Bulk M, Jonker AJ, Morrema TH, van den Berg E, Popovic M, Walter J, Kumar S, van der Lee SJ, Holstege H, Zhu X, Van Nostrand WE, Natté R, van der Weerd L, Bouwman FH, van de Berg WD, Rozemuller AJ, Hoozemans JJ. The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer's disease. Acta Neuropathol. 2020 Dec;140(6):811-830. Epub 2020 Sep 14 PubMed.

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  1. Boon et al. describe a novel type of amyloid plaque that is specifically seen in early onset Alzheimer’s disease (AD) cases who have apolipoprotein (APOE) ε4/4 status (Boon et al., 2020). The association of these plaques with capillary cerebral amyloid angiopathy (CAA; CAA type 1) and the APOE ε4 allele is another argument that APOE ε4 carriers may exhibit a type of AD distinct from that of ε4 noncarriers. In this way, this study importantly supports the concept of subtypes of AD that differ in their morphological, genetic, and clinical characteristics.

    Earlier work from our group had already indicated cases with capillary CAA that are most frequently APOE ε4 carriers and may represent a distinct type not only of CAA (Thal et al., 2002) but also of AD (Thal et al., 2010).  Work by Melissa Murray and colleagues also points to an overrepresentation of the APOE ε4 allele in a specific variant, namely the limbic-predominant variant of AD (Murray et al., 2011). 

    One could argue that the article of Boon et al. just adds one more morphologically distinct plaque type to the concert of many different plaques that all participate in the development of Aβ plaque pathology. However, in my opinion, this point of view would ignore the importance of the genetic link between distinct morphological features and AD. These very specific morphological features seen in AD cases and their association with genetic factors, as seen with the coarse-grained plaques and capillary CAA, teach us about the contribution of the genetic factor, here the APOE ε4 allele, to early onset Aβ deposition and its possible vascular/perivascular clearance, in which ApoE has been shown to play an important role (Deane et al., 2008; Thal et al., 2007). In addition, specific morphological findings help us to distinguish clinical features of AD as shown by Murray et al. (2011) and others (Tomé et al., 2020). 

    Taken together, the work of Boon et al. highlights once more the importance of the APOE ε4 allele and its specific impact on Aβ pathology, probably in the sense of a separate, APOE ε4-related subtype of AD as previously suggested (Thal et al., 2010). 

    References:

    Boon BD, Bulk M, Jonker AJ, Morrema TH, van den Berg E, Popovic M, Walter J, Kumar S, van der Lee SJ, Holstege H, Zhu X, Van Nostrand WE, Natté R, van der Weerd L, Bouwman FH, van de Berg WD, Rozemuller AJ, Hoozemans JJ. The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer's disease. Acta Neuropathol. 2020 Dec;140(6):811-830. Epub 2020 Sep 14 PubMed.

    Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008 Nov 13; PubMed.

    Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. PubMed.

    Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2002 Mar;61(3):282-93. PubMed.

    Thal DR, Larionov S, Abramowski D, Wiederhold KH, Van Dooren T, Yamaguchi H, Haass C, Van Leuven F, Staufenbiel M, Capetillo-Zarate E. Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice. Neurobiol Aging. 2007 Aug;28(8):1221-30. PubMed.

    Thal DR, Papassotiropoulos A, Saido TC, Griffin WS, Mrak RE, Kölsch H, Del Tredici K, Attems J, Ghebremedhin E. Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's disease. Acta Neuropathol. 2010 Aug;120(2):169-83. PubMed.

    Tomé SO, Vandenberghe R, Ospitalieri S, Van Schoor E, Tousseyn T, Otto M, von Arnim CA, Thal DR. Distinct molecular patterns of TDP-43 pathology in Alzheimer's disease: relationship with clinical phenotypes. Acta Neuropathol Commun. 2020 Apr 29;8(1):61. PubMed.

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