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Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.
Acta Neuropathol. 2016 08; 132(2):225-234.AN

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.

Authors+Show Affiliations

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. bu.guojun@mayo.edu.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. kanekiyo.takahisa@mayo.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27179972

Citation

Shinohara, Mitsuru, et al. "Impact of Sex and APOE4 On Cerebral Amyloid Angiopathy in Alzheimer's Disease." Acta Neuropathologica, vol. 132, no. 2, 2016, pp. 225-234.
Shinohara M, Murray ME, Frank RD, et al. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease. Acta Neuropathol. 2016;132(2):225-234.
Shinohara, M., Murray, M. E., Frank, R. D., Shinohara, M., DeTure, M., Yamazaki, Y., Tachibana, M., Atagi, Y., Davis, M. D., Liu, C. C., Zhao, N., Painter, M. M., Petersen, R. C., Fryer, J. D., Crook, J. E., Dickson, D. W., Bu, G., & Kanekiyo, T. (2016). Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease. Acta Neuropathologica, 132(2), 225-234. https://doi.org/10.1007/s00401-016-1580-y
Shinohara M, et al. Impact of Sex and APOE4 On Cerebral Amyloid Angiopathy in Alzheimer's Disease. Acta Neuropathol. 2016;132(2):225-234. PubMed PMID: 27179972.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease. AU - Shinohara,Mitsuru, AU - Murray,Melissa E, AU - Frank,Ryan D, AU - Shinohara,Motoko, AU - DeTure,Michael, AU - Yamazaki,Yu, AU - Tachibana,Masaya, AU - Atagi,Yuka, AU - Davis,Mary D, AU - Liu,Chia-Chen, AU - Zhao,Na, AU - Painter,Meghan M, AU - Petersen,Ronald C, AU - Fryer,John D, AU - Crook,Julia E, AU - Dickson,Dennis W, AU - Bu,Guojun, AU - Kanekiyo,Takahisa, Y1 - 2016/05/14/ PY - 2016/02/26/received PY - 2016/05/06/accepted PY - 2016/05/06/revised PY - 2016/5/16/entrez PY - 2016/5/18/pubmed PY - 2017/9/1/medline KW - APOE KW - Alzheimer’s disease KW - Amyloid-β KW - Cerebral amyloid angiopathy KW - Sex SP - 225 EP - 234 JF - Acta neuropathologica JO - Acta Neuropathol. VL - 132 IS - 2 N2 - 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. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/27179972/Impact_of_sex_and_APOE4_on_cerebral_amyloid_angiopathy_in_Alzheimer's_disease_ L2 - https://dx.doi.org/10.1007/s00401-016-1580-y DB - PRIME DP - Unbound Medicine ER -