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

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

doi:10.1007/s00401-016-1580-y

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

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

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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.

Original language	English (US)
Pages (from-to)	225-234
Number of pages	10
Journal	Acta neuropathologica
Volume	132
Issue number	2
DOIs	https://doi.org/10.1007/s00401-016-1580-y
State	Published - Aug 1 2016

Keywords

APOE
Alzheimer’s disease
Amyloid-β
Cerebral amyloid angiopathy
Sex

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1007/s00401-016-1580-y

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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, Murray, ME, Frank, RD, Shinohara, M, DeTure, M, Yamazaki, Y, Tachibana, M, Atagi, Y, Davis, MD, Liu, CC , Zhao, N, Painter, MM, Petersen, RC, Fryer, JD, Crook, JE, Dickson, DW , Bu, G & Kanekiyo, T 2016, 'Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease', Acta neuropathologica, vol. 132, no. 2, pp. 225-234. https://doi.org/10.1007/s00401-016-1580-y

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title = "Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer{\textquoteright}s disease",

abstract = "Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer{\textquoteright}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.",

keywords = "APOE, Alzheimer{\textquoteright}s disease, Amyloid-β, Cerebral amyloid angiopathy, Sex",

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

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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

PY - 2016/8/1

Y1 - 2016/8/1

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.

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

Abstract

Keywords

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