Klara Gawor, Sam Verrept, Geethika Arekatla, David Wouters, Alicja Ronisz, Moritz Hecht, Celeste Laureyssen, Helena Ver Donck, Bas Lahaije, Simona Ospitalieri, Mathieu Vandenbulcke, Markus Otto, Christine A. F. von Arnim, Estifanos Ghebremedhin, Bernard Hanseeuw, Rik Vandenberghe, Matthew Blaschko, Alejandro Sifrim, Kristel Sleegers, Dietmar Rudolf Thal, Sandra O. Tomé
{"title":"阿尔茨海默病及其共病：对海马变性、认知能力下降和APOE ε4的作用的影响","authors":"Klara Gawor, Sam Verrept, Geethika Arekatla, David Wouters, Alicja Ronisz, Moritz Hecht, Celeste Laureyssen, Helena Ver Donck, Bas Lahaije, Simona Ospitalieri, Mathieu Vandenbulcke, Markus Otto, Christine A. F. von Arnim, Estifanos Ghebremedhin, Bernard Hanseeuw, Rik Vandenberghe, Matthew Blaschko, Alejandro Sifrim, Kristel Sleegers, Dietmar Rudolf Thal, Sandra O. Tomé","doi":"10.1002/alz.70483","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>We analyzed 480 <i>post mortem</i> human brains (ages 50–99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (<i>APOE</i>) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while <i>APOE</i> ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>In aging individuals, amyloid β <span>peptide </span>(Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration.</li>\n \n <li>LATE-NC was the <span>strongest</span> driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration.</li>\n \n <li>Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden.</li>\n \n <li>Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology.</li>\n \n <li>Neural network models can reliably identify hippocampal pyramidal neurons on hematoxylin-stained histological slides.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0000,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70483","citationCount":"0","resultStr":"{\"title\":\"Alzheimer's disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4\",\"authors\":\"Klara Gawor, Sam Verrept, Geethika Arekatla, David Wouters, Alicja Ronisz, Moritz Hecht, Celeste Laureyssen, Helena Ver Donck, Bas Lahaije, Simona Ospitalieri, Mathieu Vandenbulcke, Markus Otto, Christine A. F. von Arnim, Estifanos Ghebremedhin, Bernard Hanseeuw, Rik Vandenberghe, Matthew Blaschko, Alejandro Sifrim, Kristel Sleegers, Dietmar Rudolf Thal, Sandra O. Tomé\",\"doi\":\"10.1002/alz.70483\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>We analyzed 480 <i>post mortem</i> human brains (ages 50–99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (<i>APOE</i>) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status.</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while <i>APOE</i> ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology.</p>\\n </section>\\n \\n <section>\\n \\n <h3> DISCUSSION</h3>\\n \\n <p>Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li>In aging individuals, amyloid β <span>peptide </span>(Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration.</li>\\n \\n <li>LATE-NC was the <span>strongest</span> driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration.</li>\\n \\n <li>Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden.</li>\\n \\n <li>Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology.</li>\\n \\n <li>Neural network models can reliably identify hippocampal pyramidal neurons on hematoxylin-stained histological slides.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":7471,\"journal\":{\"name\":\"Alzheimer's & Dementia\",\"volume\":\"21 7\",\"pages\":\"\"},\"PeriodicalIF\":13.0000,\"publicationDate\":\"2025-07-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70483\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer's & Dementia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/alz.70483\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/alz.70483","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Alzheimer's disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4
INTRODUCTION
In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors.
METHODS
We analyzed 480 post mortem human brains (ages 50–99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (APOE) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status.
RESULTS
Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while APOE ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology.
DISCUSSION
Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.
Highlights
In aging individuals, amyloid β peptide (Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration.
LATE-NC was the strongest driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration.
Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden.
Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology.
Neural network models can reliably identify hippocampal pyramidal neurons on hematoxylin-stained histological slides.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
