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01-08-2016 | Original Paper

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease

Authors: Mitsuru Shinohara, Melissa E. Murray, Ryan D. Frank, Motoko Shinohara, Michael DeTure, Yu Yamazaki, Masaya Tachibana, Yuka Atagi, Mary D. Davis, Chia-Chen Liu, Na Zhao, Meghan M. Painter, Ronald C. Petersen, John D. Fryer, Julia E. Crook, Dennis W. Dickson, Guojun Bu, Takahisa Kanekiyo

Published in: Acta Neuropathologica | Issue 2/2016

Abstract

Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE.

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Title: Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease
Authors: Mitsuru Shinohara
Melissa E. Murray
Ryan D. Frank
Motoko Shinohara
Michael DeTure
Yu Yamazaki
Masaya Tachibana
Yuka Atagi
Mary D. Davis
Chia-Chen Liu
Na Zhao
Meghan M. Painter
Ronald C. Petersen
John D. Fryer
Julia E. Crook
Dennis W. Dickson
Guojun Bu
Takahisa Kanekiyo
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 2/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1580-y

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Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease

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