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Nonlinear interaction between APOE ε4 allele load and age in the hippocampal surface of cognitively intact individuals
The ε4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is ea...
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Published in: | Human brain mapping 2021-01, Vol.42 (1), p.47-64 |
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creator | Martí‐Juan, Gerard Sanroma‐Guell, Gerard Cacciaglia, Raffaele Falcon, Carles Operto, Grégory Molinuevo, José Luis González Ballester, Miguel Ángel Gispert, Juan Domingo Piella, Gemma |
description | The ε4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE ε4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ε4‐enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi‐atlas‐based approach, obtaining high‐dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE ε4 linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE ε4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE ε4 and AD in a similar way.
We analyzed the effect of APOE e4 and other factors on hippocampal morphology in cognitively healthy and impaired subjects. Similarities between APOE effects on cognitively healthy subjects and the disease effect were found, as well as similarities between the interaction effect of APOE and age on cognitively healthy subjects, and the interaction effect between diagnosis and age on subjects covering the full disease spectrum. |
doi_str_mv | 10.1002/hbm.25202 |
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We analyzed the effect of APOE e4 and other factors on hippocampal morphology in cognitively healthy and impaired subjects. Similarities between APOE effects on cognitively healthy subjects and the disease effect were found, as well as similarities between the interaction effect of APOE and age on cognitively healthy subjects, and the interaction effect between diagnosis and age on subjects covering the full disease spectrum.</description><identifier>ISSN: 1065-9471</identifier><identifier>EISSN: 1097-0193</identifier><identifier>DOI: 10.1002/hbm.25202</identifier><identifier>PMID: 33017488</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Age ; Age Factors ; Aged ; Aged, 80 and over ; Alleles ; Alzheimer Disease - diagnostic imaging ; Alzheimer Disease - genetics ; Alzheimer Disease - pathology ; Alzheimer's disease ; APOE ; Apolipoprotein E ; Apolipoprotein E4 - genetics ; Atlases as Topic ; Atrophy ; Brain ; cognitively intact ; Cohort Studies ; Diagnosis ; Female ; Genetic Predisposition to Disease ; Health risks ; Heterozygote ; Hippocampus ; Hippocampus - anatomy & histology ; Hippocampus - diagnostic imaging ; Humans ; Impact analysis ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multivariate analysis ; Neurodegenerative diseases ; Neuroimaging - methods ; Risk analysis ; Risk factors ; Surface analysis (chemical)</subject><ispartof>Human brain mapping, 2021-01, Vol.42 (1), p.47-64</ispartof><rights>2020 The Authors. published by Wiley Periodicals LLC.</rights><rights>2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0003-4729-7182 ; 0000-0002-6155-0642</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721244/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721244/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,11562,27924,27925,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33017488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martí‐Juan, Gerard</creatorcontrib><creatorcontrib>Sanroma‐Guell, Gerard</creatorcontrib><creatorcontrib>Cacciaglia, Raffaele</creatorcontrib><creatorcontrib>Falcon, Carles</creatorcontrib><creatorcontrib>Operto, Grégory</creatorcontrib><creatorcontrib>Molinuevo, José Luis</creatorcontrib><creatorcontrib>González Ballester, Miguel Ángel</creatorcontrib><creatorcontrib>Gispert, Juan Domingo</creatorcontrib><creatorcontrib>Piella, Gemma</creatorcontrib><creatorcontrib>Alzheimer's Disease Neuroimaging Initiative</creatorcontrib><creatorcontrib>ALFA Study</creatorcontrib><title>Nonlinear interaction between APOE ε4 allele load and age in the hippocampal surface of cognitively intact individuals</title><title>Human brain mapping</title><addtitle>Hum Brain Mapp</addtitle><description>The ε4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE ε4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ε4‐enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi‐atlas‐based approach, obtaining high‐dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE ε4 linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE ε4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE ε4 and AD in a similar way.
We analyzed the effect of APOE e4 and other factors on hippocampal morphology in cognitively healthy and impaired subjects. Similarities between APOE effects on cognitively healthy subjects and the disease effect were found, as well as similarities between the interaction effect of APOE and age on cognitively healthy subjects, and the interaction effect between diagnosis and age on subjects covering the full disease spectrum.</description><subject>Age</subject><subject>Age Factors</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alleles</subject><subject>Alzheimer Disease - diagnostic imaging</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>APOE</subject><subject>Apolipoprotein E</subject><subject>Apolipoprotein E4 - genetics</subject><subject>Atlases as Topic</subject><subject>Atrophy</subject><subject>Brain</subject><subject>cognitively intact</subject><subject>Cohort Studies</subject><subject>Diagnosis</subject><subject>Female</subject><subject>Genetic Predisposition to Disease</subject><subject>Health risks</subject><subject>Heterozygote</subject><subject>Hippocampus</subject><subject>Hippocampus - anatomy & histology</subject><subject>Hippocampus - diagnostic imaging</subject><subject>Humans</subject><subject>Impact analysis</subject><subject>Magnetic Resonance Imaging</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Multivariate analysis</subject><subject>Neurodegenerative diseases</subject><subject>Neuroimaging - methods</subject><subject>Risk analysis</subject><subject>Risk factors</subject><subject>Surface analysis (chemical)</subject><issn>1065-9471</issn><issn>1097-0193</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNpdkctuFDEQRS0EIg9Y8APIEhs2nfjVbfcGKYkCQQqEBaytcnf1jCO33fRjRvNh_AbfFE8SImBRuiXVqasqXULecHbCGROna9efiFIw8YwcclbrgvFaPt_3VVnUSvMDcjRNt4xxXjL-khxIybhWxhyS7dcUg48II_VxxhGa2adIHc5bxEjPvt1c0t-_FIUQMCANCVoKMdcK8wKd10jXfhhSA_0AgU7L2EGDNHW0SavoZ7_BsNtbZ-Msrd_4doEwvSIvuiz4-lGPyY-Pl98vrorrm0-fL86ui0EYJQrj0LgOOiddW8lGNU7XGttS6VoqoaRrlJEVL42EVpsMdSCd6SQCmFaqWh6TDw--w-J6bBuM8wjBDqPvYdzZBN7-O4l-bVdpY7UWXCiVDd4_Gozp54LTbHs_NRgCREzLZDNjjNLMiIy--w-9TcsY83uZqnQlJS9lpt7-fdHTKX8yycDpA7D1AXdPc87sPmybw7b3Ydur8y_3jbwDzzOerQ</recordid><startdate>202101</startdate><enddate>202101</enddate><creator>Martí‐Juan, Gerard</creator><creator>Sanroma‐Guell, Gerard</creator><creator>Cacciaglia, Raffaele</creator><creator>Falcon, Carles</creator><creator>Operto, Grégory</creator><creator>Molinuevo, José Luis</creator><creator>González Ballester, Miguel Ángel</creator><creator>Gispert, Juan Domingo</creator><creator>Piella, Gemma</creator><general>John Wiley & Sons, Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4729-7182</orcidid><orcidid>https://orcid.org/0000-0002-6155-0642</orcidid></search><sort><creationdate>202101</creationdate><title>Nonlinear interaction between APOE ε4 allele load and age in the hippocampal surface of cognitively intact individuals</title><author>Martí‐Juan, Gerard ; Sanroma‐Guell, Gerard ; Cacciaglia, Raffaele ; Falcon, Carles ; Operto, Grégory ; Molinuevo, José Luis ; González Ballester, Miguel Ángel ; Gispert, Juan Domingo ; Piella, Gemma</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2842-8be8bfafb3bd63c4cb797ed547934243bc48361583ad783bdfa3b8f3eaa8d3493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Age</topic><topic>Age Factors</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alleles</topic><topic>Alzheimer Disease - diagnostic imaging</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>APOE</topic><topic>Apolipoprotein E</topic><topic>Apolipoprotein E4 - genetics</topic><topic>Atlases as Topic</topic><topic>Atrophy</topic><topic>Brain</topic><topic>cognitively intact</topic><topic>Cohort Studies</topic><topic>Diagnosis</topic><topic>Female</topic><topic>Genetic Predisposition to Disease</topic><topic>Health risks</topic><topic>Heterozygote</topic><topic>Hippocampus</topic><topic>Hippocampus - anatomy & histology</topic><topic>Hippocampus - diagnostic imaging</topic><topic>Humans</topic><topic>Impact analysis</topic><topic>Magnetic Resonance Imaging</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Multivariate analysis</topic><topic>Neurodegenerative diseases</topic><topic>Neuroimaging - methods</topic><topic>Risk analysis</topic><topic>Risk factors</topic><topic>Surface analysis (chemical)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martí‐Juan, Gerard</creatorcontrib><creatorcontrib>Sanroma‐Guell, Gerard</creatorcontrib><creatorcontrib>Cacciaglia, Raffaele</creatorcontrib><creatorcontrib>Falcon, Carles</creatorcontrib><creatorcontrib>Operto, Grégory</creatorcontrib><creatorcontrib>Molinuevo, José Luis</creatorcontrib><creatorcontrib>González Ballester, Miguel Ángel</creatorcontrib><creatorcontrib>Gispert, Juan Domingo</creatorcontrib><creatorcontrib>Piella, Gemma</creatorcontrib><creatorcontrib>Alzheimer's Disease Neuroimaging Initiative</creatorcontrib><creatorcontrib>ALFA Study</creatorcontrib><collection>Open Access: Wiley-Blackwell Open Access Journals</collection><collection>Wiley Online Library</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human brain mapping</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martí‐Juan, Gerard</au><au>Sanroma‐Guell, Gerard</au><au>Cacciaglia, Raffaele</au><au>Falcon, Carles</au><au>Operto, Grégory</au><au>Molinuevo, José Luis</au><au>González Ballester, Miguel Ángel</au><au>Gispert, Juan Domingo</au><au>Piella, Gemma</au><aucorp>Alzheimer's Disease Neuroimaging Initiative</aucorp><aucorp>ALFA Study</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nonlinear interaction between APOE ε4 allele load and age in the hippocampal surface of cognitively intact individuals</atitle><jtitle>Human brain mapping</jtitle><addtitle>Hum Brain Mapp</addtitle><date>2021-01</date><risdate>2021</risdate><volume>42</volume><issue>1</issue><spage>47</spage><epage>64</epage><pages>47-64</pages><issn>1065-9471</issn><eissn>1097-0193</eissn><abstract>The ε4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE ε4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ε4‐enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi‐atlas‐based approach, obtaining high‐dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE ε4 linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE ε4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE ε4 and AD in a similar way.
We analyzed the effect of APOE e4 and other factors on hippocampal morphology in cognitively healthy and impaired subjects. Similarities between APOE effects on cognitively healthy subjects and the disease effect were found, as well as similarities between the interaction effect of APOE and age on cognitively healthy subjects, and the interaction effect between diagnosis and age on subjects covering the full disease spectrum.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>33017488</pmid><doi>10.1002/hbm.25202</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0003-4729-7182</orcidid><orcidid>https://orcid.org/0000-0002-6155-0642</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Age Age Factors Aged Aged, 80 and over Alleles Alzheimer Disease - diagnostic imaging Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease APOE Apolipoprotein E Apolipoprotein E4 - genetics Atlases as Topic Atrophy Brain cognitively intact Cohort Studies Diagnosis Female Genetic Predisposition to Disease Health risks Heterozygote Hippocampus Hippocampus - anatomy & histology Hippocampus - diagnostic imaging Humans Impact analysis Magnetic Resonance Imaging Male Middle Aged Multivariate analysis Neurodegenerative diseases Neuroimaging - methods Risk analysis Risk factors Surface analysis (chemical) |
title | Nonlinear interaction between APOE ε4 allele load and age in the hippocampal surface of cognitively intact individuals |
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