Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering Variants
Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small‐vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions o...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.032689 |
| _version_ | 1827697433827606528 |
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| author | Yu‐Wen Cheng Yi‐Chu Liao Chih‐Hao Chen Chih‐Ping Chung Cathy S. J. Fann Chien‐Ching Chang Yi‐Chung Lee Sung‐Chun Tang |
| author_facet | Yu‐Wen Cheng Yi‐Chu Liao Chih‐Hao Chen Chih‐Ping Chung Cathy S. J. Fann Chien‐Ching Chang Yi‐Chung Lee Sung‐Chun Tang |
| author_sort | Yu‐Wen Cheng |
| collection | DOAJ |
| description | Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small‐vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions of the APOE genotype and Neurogenic locus notch homolog protein 3 (NOTCH3) variant position to cognitive impairment associated with CADASIL. Methods and Results Patients with the cysteine‐altering NOTCH3 variant were enrolled in a cross‐sectional study, including the Mini‐Mental State Examination (MMSE), brain magnetic resonance imaging, and APOE genotyping. Cognitive impairment was defined as an MMSE score <24. The associations between the MMSE score and genetic factors were assessed using linear regression models. Bayesian adjustment for confounding was used to identify clinical confounders. A total of 246 individuals were enrolled, among whom 210 (85%) harbored the p.R544C variant, 96 (39%) had cognitive impairment, and 150 (61%) had a history of stroke. The APOE ɛ2 allele was associated with a lower MMSE score (adjusted B, −4.090 [95% CI, −6.708 to −1.473]; P=0.023), whereas the NOTCH3 p.R544C variant was associated with a higher MMSE score (adjusted B, 2.854 [95% CI, 0.603–5.105]; P=0.0132) after adjustment for age, education, and history of ischemic stroke. Mediation analysis suggests that the associations between the APOE ɛ2 allele and MMSE score and between the NOTCH3 p.R544C variant and MMSE score are mediated by mesial temporal atrophy and white matter hyperintensity, respectively. Conclusions APOE genotype may modify cognitive impairment in CADASIL, whereby individuals carrying the APOE ɛ2 allele may present a more severe cognitive impairment. |
| first_indexed | 2024-03-10T13:08:53Z |
| format | Article |
| id | doaj.art-a9bd1c2a016446cc97097b2007db40fd |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-10T13:08:53Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-a9bd1c2a016446cc97097b2007db40fd2023-11-21T10:53:12ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-11-01122210.1161/JAHA.123.032689Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering VariantsYu‐Wen Cheng0Yi‐Chu Liao1Chih‐Hao Chen2Chih‐Ping Chung3Cathy S. J. Fann4Chien‐Ching Chang5Yi‐Chung Lee6Sung‐Chun Tang7Department of Neurology National Taiwan University Hospital Taipei TaiwanDepartment of Neurology Taipei Veterans General Hospital Taipei TaiwanDepartment of Neurology National Taiwan University Hospital Taipei TaiwanDepartment of Neurology Taipei Veterans General Hospital Taipei TaiwanInstitute of Biomedical Sciences, Academia Sinica Taipei TaiwanInstitute of Biomedical Sciences, Academia Sinica Taipei TaiwanDepartment of Neurology Taipei Veterans General Hospital Taipei TaiwanDepartment of Neurology National Taiwan University Hospital Taipei TaiwanBackground Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small‐vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions of the APOE genotype and Neurogenic locus notch homolog protein 3 (NOTCH3) variant position to cognitive impairment associated with CADASIL. Methods and Results Patients with the cysteine‐altering NOTCH3 variant were enrolled in a cross‐sectional study, including the Mini‐Mental State Examination (MMSE), brain magnetic resonance imaging, and APOE genotyping. Cognitive impairment was defined as an MMSE score <24. The associations between the MMSE score and genetic factors were assessed using linear regression models. Bayesian adjustment for confounding was used to identify clinical confounders. A total of 246 individuals were enrolled, among whom 210 (85%) harbored the p.R544C variant, 96 (39%) had cognitive impairment, and 150 (61%) had a history of stroke. The APOE ɛ2 allele was associated with a lower MMSE score (adjusted B, −4.090 [95% CI, −6.708 to −1.473]; P=0.023), whereas the NOTCH3 p.R544C variant was associated with a higher MMSE score (adjusted B, 2.854 [95% CI, 0.603–5.105]; P=0.0132) after adjustment for age, education, and history of ischemic stroke. Mediation analysis suggests that the associations between the APOE ɛ2 allele and MMSE score and between the NOTCH3 p.R544C variant and MMSE score are mediated by mesial temporal atrophy and white matter hyperintensity, respectively. Conclusions APOE genotype may modify cognitive impairment in CADASIL, whereby individuals carrying the APOE ɛ2 allele may present a more severe cognitive impairment.https://www.ahajournals.org/doi/10.1161/JAHA.123.032689APOECADASILcerebral small‐vessel diseaseNOTCH3vascular cognitive impairment |
| spellingShingle | Yu‐Wen Cheng Yi‐Chu Liao Chih‐Hao Chen Chih‐Ping Chung Cathy S. J. Fann Chien‐Ching Chang Yi‐Chung Lee Sung‐Chun Tang Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering Variants Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease APOE CADASIL cerebral small‐vessel disease NOTCH3 vascular cognitive impairment |
| title | Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering Variants |
| title_full | Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering Variants |
| title_fullStr | Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering Variants |
| title_full_unstemmed | Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering Variants |
| title_short | Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine‐Altering Variants |
| title_sort | contribution of the apoe genotype to cognitive impairment in individuals with notch3 cysteine altering variants |
| topic | APOE CADASIL cerebral small‐vessel disease NOTCH3 vascular cognitive impairment |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.032689 |
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