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

• DOI: 10.1007/s00401-018-1866-3
• Publication Date: 2018-05-16T09:48:33Z
• Authors: David M. A. Mann; Yvonne S. Davidson; Andrew C. Robinson; Nancy Allen; Tadafumi Hashimoto; Anna Richardson; Matthew Jones; Julie S. Snowden; Neil Pendleton; Marie-Claude Potier; Annie Laquerrière; Vee Prasher; Takeshi Iwatsubo; Andre Strydom
• Keywords: Adult; Male; Amyloid; Genotype; APP mutations; Down syndrome; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Mutation, Missense; 610; Amyloid plaques; Plaque, Amyloid; Amyloid beta-Protein Precursor; 03 medical and health sciences; Apolipoproteins E; 0302 clinical medicine; Gene Frequency; Alzheimer Disease; Gene Duplication; Journal Article; Humans; Cerebral amyloid angiopathy; Aged; Aged, 80 and over; Original Paper; [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Middle Aged; 3. Good health; Cerebral Amyloid Angiopathy; Blood Vessels; Female; Down Syndrome; Alzheimer’s disease

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.