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Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease.
Acta Neuropathol 2018; 136(4):569-587AN

Abstract

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more 'aggressive' form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.

Authors+Show Affiliations

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, University of Manchester, Salford, UK. david.mann@manchester.ac.uk.Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, University of Manchester, Salford, UK.Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, University of Manchester, Salford, UK.Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, University of Manchester, Salford, UK.Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, UK.Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, UK.Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, University of Manchester, Salford, UK. Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, UK.Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, University of Manchester, Salford, UK.ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, UPMC, Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, Paris, France.Department of Pathology, Rouen University Hospital, Rouen, France. Normandie Univ, UNIROUEN, CHU Rouen, INSERM U1245, Team 4, Neovasc, 76000, Rouen, France.Birmingham Community NHS Trust, The Greenfields, 30 Brookfield Road, Birmingham, B30 3QY, UK.Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London, UK. Division of Psychiatry, University College London, 147 Tottenham Court Road, London, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29770843

Citation

Mann, David M A., et al. "Patterns and Severity of Vascular Amyloid in Alzheimer's Disease Associated With Duplications and Missense Mutations in APP Gene, Down Syndrome and Sporadic Alzheimer's Disease." Acta Neuropathologica, vol. 136, no. 4, 2018, pp. 569-587.
Mann DMA, Davidson YS, Robinson AC, et al. Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease. Acta Neuropathol. 2018;136(4):569-587.
Mann, D. M. A., Davidson, Y. S., Robinson, A. C., Allen, N., Hashimoto, T., Richardson, A., ... Strydom, A. (2018). Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease. Acta Neuropathologica, 136(4), pp. 569-587. doi:10.1007/s00401-018-1866-3.
Mann DMA, et al. Patterns and Severity of Vascular Amyloid in Alzheimer's Disease Associated With Duplications and Missense Mutations in APP Gene, Down Syndrome and Sporadic Alzheimer's Disease. Acta Neuropathol. 2018;136(4):569-587. PubMed PMID: 29770843.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease. AU - Mann,David M A, AU - Davidson,Yvonne S, AU - Robinson,Andrew C, AU - Allen,Nancy, AU - Hashimoto,Tadafumi, AU - Richardson,Anna, AU - Jones,Matthew, AU - Snowden,Julie S, AU - Pendleton,Neil, AU - Potier,Marie-Claude, AU - Laquerrière,Annie, AU - Prasher,Vee, AU - Iwatsubo,Takeshi, AU - Strydom,Andre, Y1 - 2018/05/16/ PY - 2018/02/15/received PY - 2018/05/10/accepted PY - 2018/05/04/revised PY - 2018/5/18/pubmed PY - 2018/5/18/medline PY - 2018/5/18/entrez KW - APP mutations KW - Alzheimer’s disease KW - Amyloid plaques KW - Cerebral amyloid angiopathy KW - Down syndrome SP - 569 EP - 587 JF - Acta neuropathologica JO - Acta Neuropathol. VL - 136 IS - 4 N2 - In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more 'aggressive' form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/29770843/Patterns_and_severity_of_vascular_amyloid_in_Alzheimer's_disease_associated_with_duplications_and_missense_mutations_in_APP_gene_Down_syndrome_and_sporadic_Alzheimer's_disease_ L2 - https://dx.doi.org/10.1007/s00401-018-1866-3 DB - PRIME DP - Unbound Medicine ER -