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 Carl Petersen, John D. Fryer, Juliana Crook, Dennis W Dickson, Guojun D Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalActa Neuropathologica
DOIs
StateAccepted/In press - May 14 2016

Fingerprint

Cerebral Amyloid Angiopathy
Alzheimer Disease
Apolipoproteins E
Temporal Lobe
Amyloid
Detergents
Cerebrovascular Disorders
Neurofibrillary Tangles
Visual Cortex
Sex Characteristics

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease. / Shinohara, Mitsuru; Murray, Melissa E; Frank, Ryan D.; Shinohara, Motoko; Deture, Michael; Yamazaki, Yu; Tachibana, Masaya; Atagi, Yuka; Davis, Mary D.; Liu, Chia-Chen; Zhao, Na; Painter, Meghan M.; Petersen, Ronald Carl; Fryer, John D.; Crook, Juliana; Dickson, Dennis W; Bu, Guojun D; Kanekiyo, Takahisa.

In: Acta Neuropathologica, 14.05.2016, p. 1-10.

Research output: Contribution to journalArticle

Shinohara, Mitsuru ; Murray, Melissa E ; Frank, Ryan D. ; Shinohara, Motoko ; Deture, Michael ; Yamazaki, Yu ; Tachibana, Masaya ; Atagi, Yuka ; Davis, Mary D. ; Liu, Chia-Chen ; Zhao, Na ; Painter, Meghan M. ; Petersen, Ronald Carl ; Fryer, John D. ; Crook, Juliana ; Dickson, Dennis W ; Bu, Guojun D ; Kanekiyo, Takahisa. / Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease. In: Acta Neuropathologica. 2016 ; pp. 1-10.
@article{53ae8c5c5da44a77bfac6b25b8db6ed3,
title = "Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease",
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.",
keywords = "Alzheimer’s disease, Amyloid-β, APOE, 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 Chia-Chen Liu and Na Zhao and Painter, {Meghan M.} and Petersen, {Ronald Carl} and Fryer, {John D.} and Juliana Crook and Dickson, {Dennis W} and Bu, {Guojun D} and Takahisa Kanekiyo",
year = "2016",
month = "5",
day = "14",
doi = "10.1007/s00401-016-1580-y",
language = "English (US)",
pages = "1--10",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",

}

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 Carl

AU - Fryer, John D.

AU - Crook, Juliana

AU - Dickson, Dennis W

AU - Bu, Guojun D

AU - Kanekiyo, Takahisa

PY - 2016/5/14

Y1 - 2016/5/14

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.

KW - Alzheimer’s disease

KW - Amyloid-β

KW - APOE

KW - Cerebral amyloid angiopathy

KW - Sex

UR - http://www.scopus.com/inward/record.url?scp=84968531504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84968531504&partnerID=8YFLogxK

U2 - 10.1007/s00401-016-1580-y

DO - 10.1007/s00401-016-1580-y

M3 - Article

C2 - 27179972

AN - SCOPUS:84968531504

SP - 1

EP - 10

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

ER -