O2‐03‐03: Phenotypic and genetic subclassification of Alzheimer's diseaseстатья из журнала
Аннотация: Two different types of Alzheimer's disease (AD)-related cerebral amyloid angiopathy (CAA) can be distinguished by the presence or absence of capillary amyloid β-protein (Aβ)-deposition. Genetically, CAA-type 1 with capillary CAA is strongly associated with the apolipoprotein E (APOE) ϵ4-allele, while CAA-type 2 lacking capillary Aβ did not show this association. The objective of this study was to test whether there exist further phenotypic and genotypic differences between CAA-type 1 and CAA-type 2 cases that may allow the distinction of different types of AD. Autopsy brains from 58 AD cases and 254 non-demented elderly controls were studied neuropathologically for vascular and parenchymal Aβ-deposition and for the expansion of neurofibrillary tangles as represented by the Braak-stage. In selected cases the astroglial expression of the glutamate transporters EAAT-1 and EAAT-2 was studied immunohistochemically. Double label immunohistochemistry was used to demonstrate the relationship between capillary CAA and EAAT-2 expression in astrocytes.Genotyping of the following polymorphisms was performed: APOE4-allele, CYP46A1 rs7157609 and CH25H rs13500 and rs1131706. Logistic regression analysis was used to study the association of these polymorphisms with CAA-type 1 and CAA-type 2. The CAA-type 1-related form of AD was also associated with the CH25H rs1131706 TT genotype and with a loss of perivascular, excitatory amino acid transporter (EAAT-2) expressing astrocytes in the cortex. In contrast, AD cases lacking capillary Aβ-deposition showed an association with the G-allele of the CYP46A1 rs7157609 polymorphism and exhibited more widespread neurofibrillary tangle (NFT) pathology in relation to the expansion of Aβ-deposition than AD cases with CAA-type 1. One form of sporadic AD is characterized by capillary CAA, astroglial alterations and is genetically associated with the APOE ϵ4-allele and the CH25H*2 TT genotype, whereas the second form of sporadic AD lacks capillary CAA, exhibits a NFT predominant pattern of AD-related lesions and is associated with the CYP46A1 rs7157609 G-allele. AD cases with an additional pathology (e.g. vascular lesions and/ or other tauopathies) segregated clinicopathologically as an additional “mixed dementia” type of AD.This subclassification points to distinct pathogenetic features in subtypes of sporadic AD which may have therapeutic relevance in the future.
Год издания: 2009
Авторы: Dietmar Rudolf Thal, Heike Koelsch, Andreas Papassotiropoulos, Takaomi C. Saido, Sue Griffin, Tom Van Dooren, Fred Van Leuven, Estifanos Ghebremedhin
Издательство: Wiley
Источник: Alzheimer s & Dementia
Ключевые слова: Alzheimer's disease research and treatments
Открытый доступ: bronze
Том: 5
Выпуск: 4S_Part_4