Fabricio Ferreira de Oliveira, Thais Emanuele de Almeida, Alessandra Felix Cardoso, Tathyane Chaves Faria, Guilherme Sampaio Souza, Sandro Soares de Almeida, Diego Robles Mazzotti, Elizabeth Suchi Chen, Marilia Cardoso Smith, Paulo Henrique Ferreira Bertolucci
{"title":"apoe介导的GRIN1和GRIN2B启动子变异与阿尔茨海默病痴呆的行为症状和发病年龄的关联","authors":"Fabricio Ferreira de Oliveira, Thais Emanuele de Almeida, Alessandra Felix Cardoso, Tathyane Chaves Faria, Guilherme Sampaio Souza, Sandro Soares de Almeida, Diego Robles Mazzotti, Elizabeth Suchi Chen, Marilia Cardoso Smith, Paulo Henrique Ferreira Bertolucci","doi":"10.1080/01616412.2025.2511095","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>To determine associations of alleles of rs11146020 (<i>GRIN1</i>) and rs3764028 (<i>GRIN2B</i>), encoding subunits of the N-methyl-D-aspartate (NMDA) receptor, with the age at Alzheimer's disease dementia onset and with behavioral symptoms in each dementia stage, mediated by <i>APOE</i> (apolipoprotein E gene) ε4 carriership.</p><p><strong>Methods: </strong>A cross-sectional study involving consecutive outpatients with Alzheimer's disease dementia assessed for demographic features, Clinical Dementia Rating, and the Neuropsychiatric Inventory, genotyped for rs7412 and rs429358 (<i>APOE</i>, Real-Time Polymerase Chain Reactions), rs11146020 and rs3764028 (Polymerase Chain Reactions). Genetic variants were associated with the age at dementia onset, and with behavioral symptoms at each dementia stage (adjusted for sex, age at dementia onset, and psychotropic drug therapy).</p><p><strong>Results: </strong>Considering 210 patients: 68.1% were women, 52.4% were <i>APOE</i>-ε4 carriers, all single nucleotide polymorphisms in Hardy-Weinberg equilibrium. <i>APOE</i>-ε4/ε4 carriers had earlier dementia onset, as well as carriers of rs11146020-G or rs3764028-C, particularly when they were <i>APOE</i>-ε4 non-carriers, <i>p</i> < 0.001. Mildly impaired rs11146020-G carriers had less aberrant motor behavior when they were <i>APOE</i>-ε4 carriers (<i>p</i> = 0.044). For moderately impaired rs3764028-A carriers, <i>APOE</i>-ε4 carriers had higher Neuropsychiatric Inventory total scores (<i>p</i> = 0.001), while <i>APOE</i>-ε4 non-carriers had more delusions (<i>p</i> = 0.003). Still in moderate dementia, rs11146020-C carriers had more aberrant motor behavior when they were <i>APOE</i>-ε4 carriers (<i>p</i> = 0.032), and rs11146020-G carriers had less apathy (<i>p</i> = 0.039) and more disinhibition (<i>p</i> = 0.032) when they were <i>APOE</i>-ε4 carriers. No associations survived corrections for false discovery rates in severe dementia.</p><p><strong>Conclusion: </strong>Alleles rs11146020-G and rs3764028-C lead to earlier dementia onset with a mostly milder disease course while softening the behavioral burden.</p>","PeriodicalId":19131,"journal":{"name":"Neurological Research","volume":" ","pages":"1013-1022"},"PeriodicalIF":1.5000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"<i>APOE</i>-mediated associations of promoter variants of <i>GRIN1</i> and <i>GRIN2B</i> with behavioral symptoms and age at onset of Alzheimer's disease dementia.\",\"authors\":\"Fabricio Ferreira de Oliveira, Thais Emanuele de Almeida, Alessandra Felix Cardoso, Tathyane Chaves Faria, Guilherme Sampaio Souza, Sandro Soares de Almeida, Diego Robles Mazzotti, Elizabeth Suchi Chen, Marilia Cardoso Smith, Paulo Henrique Ferreira Bertolucci\",\"doi\":\"10.1080/01616412.2025.2511095\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>To determine associations of alleles of rs11146020 (<i>GRIN1</i>) and rs3764028 (<i>GRIN2B</i>), encoding subunits of the N-methyl-D-aspartate (NMDA) receptor, with the age at Alzheimer's disease dementia onset and with behavioral symptoms in each dementia stage, mediated by <i>APOE</i> (apolipoprotein E gene) ε4 carriership.</p><p><strong>Methods: </strong>A cross-sectional study involving consecutive outpatients with Alzheimer's disease dementia assessed for demographic features, Clinical Dementia Rating, and the Neuropsychiatric Inventory, genotyped for rs7412 and rs429358 (<i>APOE</i>, Real-Time Polymerase Chain Reactions), rs11146020 and rs3764028 (Polymerase Chain Reactions). Genetic variants were associated with the age at dementia onset, and with behavioral symptoms at each dementia stage (adjusted for sex, age at dementia onset, and psychotropic drug therapy).</p><p><strong>Results: </strong>Considering 210 patients: 68.1% were women, 52.4% were <i>APOE</i>-ε4 carriers, all single nucleotide polymorphisms in Hardy-Weinberg equilibrium. <i>APOE</i>-ε4/ε4 carriers had earlier dementia onset, as well as carriers of rs11146020-G or rs3764028-C, particularly when they were <i>APOE</i>-ε4 non-carriers, <i>p</i> < 0.001. Mildly impaired rs11146020-G carriers had less aberrant motor behavior when they were <i>APOE</i>-ε4 carriers (<i>p</i> = 0.044). For moderately impaired rs3764028-A carriers, <i>APOE</i>-ε4 carriers had higher Neuropsychiatric Inventory total scores (<i>p</i> = 0.001), while <i>APOE</i>-ε4 non-carriers had more delusions (<i>p</i> = 0.003). Still in moderate dementia, rs11146020-C carriers had more aberrant motor behavior when they were <i>APOE</i>-ε4 carriers (<i>p</i> = 0.032), and rs11146020-G carriers had less apathy (<i>p</i> = 0.039) and more disinhibition (<i>p</i> = 0.032) when they were <i>APOE</i>-ε4 carriers. No associations survived corrections for false discovery rates in severe dementia.</p><p><strong>Conclusion: </strong>Alleles rs11146020-G and rs3764028-C lead to earlier dementia onset with a mostly milder disease course while softening the behavioral burden.</p>\",\"PeriodicalId\":19131,\"journal\":{\"name\":\"Neurological Research\",\"volume\":\" \",\"pages\":\"1013-1022\"},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurological Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/01616412.2025.2511095\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/29 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurological Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/01616412.2025.2511095","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/29 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
APOE-mediated associations of promoter variants of GRIN1 and GRIN2B with behavioral symptoms and age at onset of Alzheimer's disease dementia.
Objective: To determine associations of alleles of rs11146020 (GRIN1) and rs3764028 (GRIN2B), encoding subunits of the N-methyl-D-aspartate (NMDA) receptor, with the age at Alzheimer's disease dementia onset and with behavioral symptoms in each dementia stage, mediated by APOE (apolipoprotein E gene) ε4 carriership.
Methods: A cross-sectional study involving consecutive outpatients with Alzheimer's disease dementia assessed for demographic features, Clinical Dementia Rating, and the Neuropsychiatric Inventory, genotyped for rs7412 and rs429358 (APOE, Real-Time Polymerase Chain Reactions), rs11146020 and rs3764028 (Polymerase Chain Reactions). Genetic variants were associated with the age at dementia onset, and with behavioral symptoms at each dementia stage (adjusted for sex, age at dementia onset, and psychotropic drug therapy).
Results: Considering 210 patients: 68.1% were women, 52.4% were APOE-ε4 carriers, all single nucleotide polymorphisms in Hardy-Weinberg equilibrium. APOE-ε4/ε4 carriers had earlier dementia onset, as well as carriers of rs11146020-G or rs3764028-C, particularly when they were APOE-ε4 non-carriers, p < 0.001. Mildly impaired rs11146020-G carriers had less aberrant motor behavior when they were APOE-ε4 carriers (p = 0.044). For moderately impaired rs3764028-A carriers, APOE-ε4 carriers had higher Neuropsychiatric Inventory total scores (p = 0.001), while APOE-ε4 non-carriers had more delusions (p = 0.003). Still in moderate dementia, rs11146020-C carriers had more aberrant motor behavior when they were APOE-ε4 carriers (p = 0.032), and rs11146020-G carriers had less apathy (p = 0.039) and more disinhibition (p = 0.032) when they were APOE-ε4 carriers. No associations survived corrections for false discovery rates in severe dementia.
Conclusion: Alleles rs11146020-G and rs3764028-C lead to earlier dementia onset with a mostly milder disease course while softening the behavioral burden.
期刊介绍：
Neurological Research is an international, peer-reviewed journal for reporting both basic and clinical research in the fields of neurosurgery, neurology, neuroengineering and neurosciences. It provides a medium for those who recognize the wider implications of their work and who wish to be informed of the relevant experience of others in related and more distant fields.
The scope of the journal includes:
•Stem cell applications
•Molecular neuroscience
•Neuropharmacology
•Neuroradiology
•Neurochemistry
•Biomathematical models
•Endovascular neurosurgery
•Innovation in neurosurgery.
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