Cerebrovascular reactivity and plasma p-tau181 in Alzheimer's disease: Insights into APOE-related vascular phenotypes

IF 7.4 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2026-06-30 DOI:10.1002/trc2.70250

Martina Gaia Di Donna, Maria Rosaria Bagnato, Chiara Giuseppina Bonomi, Caterina Motta, Diego Centonze, Alessandro Martorana, Marina Diomedi

{"title":"Cerebrovascular reactivity and plasma p-tau181 in Alzheimer's disease: Insights into APOE-related vascular phenotypes","authors":"Martina Gaia Di Donna, Maria Rosaria Bagnato, Chiara Giuseppina Bonomi, Caterina Motta, Diego Centonze, Alessandro Martorana, Marina Diomedi","doi":"10.1002/trc2.70250","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Vascular dysfunction is increasingly recognized as a key contributor to Alzheimer's disease (AD). This study explored cerebrovascular reactivity (CVR), measured by the breath-holding index (BHI) via Transcranial Doppler (TCD), in relation to plasma AD biomarkers, metabolic dysfunction, cardiovascular burden, and apolipoprotein E (APOE) genotype.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>We enrolled 64 patients with cerebrospinal fluid (CSF)-confirmed AD (30 APOE ε3, 34 APOE ε4) and 28 age-matched healthy controls in a cross-sectional blinded study. All participants underwent TCD to assess middle cerebral artery flow velocity and BHI. AD patients were further evaluated for insulin resistance (TyG index), magnetic resonance imaging markers of small vessel disease (SVD), and plasma biomarkers (phosphorylated tau 181 [p-tau181], amyloid beta [Aβ]42/Aβ40 ratio – AmyR). Multivariate regressions examined associations between BHI and AD-related parameters, stratified by APOE genotype.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>BHI was significantly reduced in both AD groups compared to controls (<i>p</i> < 0.001), with no difference between ε3 and ε4 carriers. In ε3 patients, lower BHI was independently associated with higher plasma p-tau181. In the MRI subgroup analysis, ε3 patients showed a negative correlation between BHI and both TyG and mCSVD while showing a positive correlation with AmyR. None of these associations were observed in ε4 carriers.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our findings indicate that CVR impairment is present across AD genotypes but more strongly linked to AD pathology and vascular-metabolic dysfunction in APOE ε3 carriers. CVR may represent a non-invasive biomarker of early vascular contributions to cognitive decline in AD.</p>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":""},"PeriodicalIF":7.4000,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70250","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/trc2.70250","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

INTRODUCTION

Vascular dysfunction is increasingly recognized as a key contributor to Alzheimer's disease (AD). This study explored cerebrovascular reactivity (CVR), measured by the breath-holding index (BHI) via Transcranial Doppler (TCD), in relation to plasma AD biomarkers, metabolic dysfunction, cardiovascular burden, and apolipoprotein E (APOE) genotype.

METHODS

We enrolled 64 patients with cerebrospinal fluid (CSF)-confirmed AD (30 APOE ε3, 34 APOE ε4) and 28 age-matched healthy controls in a cross-sectional blinded study. All participants underwent TCD to assess middle cerebral artery flow velocity and BHI. AD patients were further evaluated for insulin resistance (TyG index), magnetic resonance imaging markers of small vessel disease (SVD), and plasma biomarkers (phosphorylated tau 181 [p-tau181], amyloid beta [Aβ]42/Aβ40 ratio – AmyR). Multivariate regressions examined associations between BHI and AD-related parameters, stratified by APOE genotype.

RESULTS

BHI was significantly reduced in both AD groups compared to controls (p < 0.001), with no difference between ε3 and ε4 carriers. In ε3 patients, lower BHI was independently associated with higher plasma p-tau181. In the MRI subgroup analysis, ε3 patients showed a negative correlation between BHI and both TyG and mCSVD while showing a positive correlation with AmyR. None of these associations were observed in ε4 carriers.

DISCUSSION

Our findings indicate that CVR impairment is present across AD genotypes but more strongly linked to AD pathology and vascular-metabolic dysfunction in APOE ε3 carriers. CVR may represent a non-invasive biomarker of early vascular contributions to cognitive decline in AD.

Abstract Image

查看原文本刊更多论文

阿尔茨海默病的脑血管反应性和血浆p-tau181: apoe相关血管表型的见解

血管功能障碍越来越被认为是阿尔茨海默病（AD）的一个关键因素。本研究探讨了脑血管反应性（CVR）与血浆AD生物标志物、代谢功能障碍、心血管负担和载脂蛋白E （APOE）基因型的关系，通过经颅多普勒（TCD）憋气指数（BHI）测量。方法采用横断面盲法研究64例脑脊液确诊AD患者（30例APOE ε3, 34例APOE ε4）和28例年龄匹配的健康对照。所有参与者均行TCD评估大脑中动脉血流速度和BHI。进一步评估AD患者的胰岛素抵抗（TyG指数）、小血管疾病磁共振成像标志物（SVD）和血浆生物标志物（磷酸化tau181 [p-tau181]、β淀粉样蛋白[Aβ]42/Aβ40比值- AmyR）。通过APOE基因型分层，多变量回归分析了BHI和ad相关参数之间的关系。结果与对照组相比，两个AD组的BHI显著降低（p < 0.001），而ε3和ε4携带者之间无差异。在ε3患者中，较低的BHI与较高的血浆p-tau181独立相关。在MRI亚组分析中，ε3患者BHI与TyG、mCSVD呈负相关，与AmyR呈正相关。在ε4携带者中没有观察到这些关联。我们的研究结果表明，CVR损伤存在于AD基因型中，但与APOE ε3携带者的AD病理和血管代谢功能障碍有更强的联系。CVR可能是早期血管对AD患者认知能力下降的一种非侵入性生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.