Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort
Background The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined. Method We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associati...
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| Veröffentlicht in: | Alzheimer's & dementia 2023-12, Vol.19 (S10), p.n/a |
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| creator | Lorenzini, Luigi Maranzano, Alessio Tranfa, Mario Collij, Lyduine E. Sudre, Carole H Wolz, Robin Haller, Sven Blennow, Kaj Frisoni, Giovanni B Payoux, Pierre Martinez‐Lage, Pablo Ewers, Michael Chetelat, Gael Waldman, Adam Wardlaw, Joanna M Fox, Nick C Ritchie, Craig W Scheltens, Philip Visser, Pieter Jelle Wink, Alle Meije Mutsaerts, Henk‐Jan Gispert, Juan Domingo Ingala, Silvia Barkhof, Frederik |
| description | Background
The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.
Method
We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.
Result
Higher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p |
| doi_str_mv | 10.1002/alz.081655 |
| format | Article |
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The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.
Method
We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.
Result
Higher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p<0.001) and higher P‐tau181 (ß = 0.21; p<0.001). Aß1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2). We found stronger association between Aß1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes. Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aß1‐42 (indirect effect: ß = ‐0.03; p<0.001). Aß1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aß1‐42 on P‐tau181 levels (ß = ‐0.14; p<0.001) and HCV (ß = 0.06; p<0.05), and of P‐tau181 levels onto HCV (ß = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: ß = 0.36; p < 0.05) and HCV (indirect effect: ß = ‐0.24; p < 0.05) through Aß1‐42 was observed.
Conclusion
Expression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.]]></description><identifier>ISSN: 1552-5260</identifier><identifier>EISSN: 1552-5279</identifier><identifier>DOI: 10.1002/alz.081655</identifier><language>eng</language><ispartof>Alzheimer's & dementia, 2023-12, Vol.19 (S10), p.n/a</ispartof><rights>2023 the Alzheimer's Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Falz.081655$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Falz.081655$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27926,27927,45576,45577</link.rule.ids></links><search><creatorcontrib>Lorenzini, Luigi</creatorcontrib><creatorcontrib>Maranzano, Alessio</creatorcontrib><creatorcontrib>Tranfa, Mario</creatorcontrib><creatorcontrib>Collij, Lyduine E.</creatorcontrib><creatorcontrib>Sudre, Carole H</creatorcontrib><creatorcontrib>Wolz, Robin</creatorcontrib><creatorcontrib>Haller, Sven</creatorcontrib><creatorcontrib>Blennow, Kaj</creatorcontrib><creatorcontrib>Frisoni, Giovanni B</creatorcontrib><creatorcontrib>Payoux, Pierre</creatorcontrib><creatorcontrib>Martinez‐Lage, Pablo</creatorcontrib><creatorcontrib>Ewers, Michael</creatorcontrib><creatorcontrib>Chetelat, Gael</creatorcontrib><creatorcontrib>Waldman, Adam</creatorcontrib><creatorcontrib>Wardlaw, Joanna M</creatorcontrib><creatorcontrib>Fox, Nick C</creatorcontrib><creatorcontrib>Ritchie, Craig W</creatorcontrib><creatorcontrib>Scheltens, Philip</creatorcontrib><creatorcontrib>Visser, Pieter Jelle</creatorcontrib><creatorcontrib>Wink, Alle Meije</creatorcontrib><creatorcontrib>Mutsaerts, Henk‐Jan</creatorcontrib><creatorcontrib>Gispert, Juan Domingo</creatorcontrib><creatorcontrib>Ingala, Silvia</creatorcontrib><creatorcontrib>Barkhof, Frederik</creatorcontrib><title>Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort</title><title>Alzheimer's & dementia</title><description><![CDATA[Background
The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.
Method
We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.
Result
Higher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p<0.001) and higher P‐tau181 (ß = 0.21; p<0.001). Aß1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2). We found stronger association between Aß1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes. Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aß1‐42 (indirect effect: ß = ‐0.03; p<0.001). Aß1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aß1‐42 on P‐tau181 levels (ß = ‐0.14; p<0.001) and HCV (ß = 0.06; p<0.05), and of P‐tau181 levels onto HCV (ß = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: ß = 0.36; p < 0.05) and HCV (indirect effect: ß = ‐0.24; p < 0.05) through Aß1‐42 was observed.
Conclusion
Expression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.]]></description><issn>1552-5260</issn><issn>1552-5279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp90LFOwzAQBmALgUQpLDyBZ6QU24ntmC0qBSpVggEYWCLHsRsjN67sVKideA1ejychNBUj093w3X_SD8AlRhOMELmWbjdBOWaUHoERppQklHBx_LczdArOYnxHKOsZHYHwKqPaOBmg8m0XbLXprG9h52HXaLgOWjnbWiUdLNyu0Xalw_fnV4S1jVrGXsiu8c4v90Q1sl3qeAPnbbTLpovQBL_aJ82eitv-ReNDdw5OjHRRXxzmGLzczZ6nD8ni8X4-LRaJwjilCSOGIpXXNVecVUIIKitjSC1JlmrJWYYoz7OcC5yqzOSZJKmsqBBcYcEYZukYXA25KvgYgzblOtiVDNsSo_K3rbJvqxza6jEe8Id1evuPLIvF2-HmB6XpbqM</recordid><startdate>202312</startdate><enddate>202312</enddate><creator>Lorenzini, Luigi</creator><creator>Maranzano, Alessio</creator><creator>Tranfa, Mario</creator><creator>Collij, Lyduine E.</creator><creator>Sudre, Carole H</creator><creator>Wolz, Robin</creator><creator>Haller, Sven</creator><creator>Blennow, Kaj</creator><creator>Frisoni, Giovanni B</creator><creator>Payoux, Pierre</creator><creator>Martinez‐Lage, Pablo</creator><creator>Ewers, Michael</creator><creator>Chetelat, Gael</creator><creator>Waldman, Adam</creator><creator>Wardlaw, Joanna M</creator><creator>Fox, Nick C</creator><creator>Ritchie, Craig W</creator><creator>Scheltens, Philip</creator><creator>Visser, Pieter Jelle</creator><creator>Wink, Alle Meije</creator><creator>Mutsaerts, Henk‐Jan</creator><creator>Gispert, Juan Domingo</creator><creator>Ingala, Silvia</creator><creator>Barkhof, Frederik</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>202312</creationdate><title>Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort</title><author>Lorenzini, Luigi ; Maranzano, Alessio ; Tranfa, Mario ; Collij, Lyduine E. ; Sudre, Carole H ; Wolz, Robin ; Haller, Sven ; Blennow, Kaj ; Frisoni, Giovanni B ; Payoux, Pierre ; Martinez‐Lage, Pablo ; Ewers, Michael ; Chetelat, Gael ; Waldman, Adam ; Wardlaw, Joanna M ; Fox, Nick C ; Ritchie, Craig W ; Scheltens, Philip ; Visser, Pieter Jelle ; Wink, Alle Meije ; Mutsaerts, Henk‐Jan ; Gispert, Juan Domingo ; Ingala, Silvia ; Barkhof, Frederik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1135-62f50c8dd7c76b9995abff2da243ea7640578487913c4f84a23ab5997c1966163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lorenzini, Luigi</creatorcontrib><creatorcontrib>Maranzano, Alessio</creatorcontrib><creatorcontrib>Tranfa, Mario</creatorcontrib><creatorcontrib>Collij, Lyduine E.</creatorcontrib><creatorcontrib>Sudre, Carole H</creatorcontrib><creatorcontrib>Wolz, Robin</creatorcontrib><creatorcontrib>Haller, Sven</creatorcontrib><creatorcontrib>Blennow, Kaj</creatorcontrib><creatorcontrib>Frisoni, Giovanni B</creatorcontrib><creatorcontrib>Payoux, Pierre</creatorcontrib><creatorcontrib>Martinez‐Lage, Pablo</creatorcontrib><creatorcontrib>Ewers, Michael</creatorcontrib><creatorcontrib>Chetelat, Gael</creatorcontrib><creatorcontrib>Waldman, Adam</creatorcontrib><creatorcontrib>Wardlaw, Joanna M</creatorcontrib><creatorcontrib>Fox, Nick C</creatorcontrib><creatorcontrib>Ritchie, Craig W</creatorcontrib><creatorcontrib>Scheltens, Philip</creatorcontrib><creatorcontrib>Visser, Pieter Jelle</creatorcontrib><creatorcontrib>Wink, Alle Meije</creatorcontrib><creatorcontrib>Mutsaerts, Henk‐Jan</creatorcontrib><creatorcontrib>Gispert, Juan Domingo</creatorcontrib><creatorcontrib>Ingala, Silvia</creatorcontrib><creatorcontrib>Barkhof, Frederik</creatorcontrib><collection>CrossRef</collection><jtitle>Alzheimer's & dementia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lorenzini, Luigi</au><au>Maranzano, Alessio</au><au>Tranfa, Mario</au><au>Collij, Lyduine E.</au><au>Sudre, Carole H</au><au>Wolz, Robin</au><au>Haller, Sven</au><au>Blennow, Kaj</au><au>Frisoni, Giovanni B</au><au>Payoux, Pierre</au><au>Martinez‐Lage, Pablo</au><au>Ewers, Michael</au><au>Chetelat, Gael</au><au>Waldman, Adam</au><au>Wardlaw, Joanna M</au><au>Fox, Nick C</au><au>Ritchie, Craig W</au><au>Scheltens, Philip</au><au>Visser, Pieter Jelle</au><au>Wink, Alle Meije</au><au>Mutsaerts, Henk‐Jan</au><au>Gispert, Juan Domingo</au><au>Ingala, Silvia</au><au>Barkhof, Frederik</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort</atitle><jtitle>Alzheimer's & dementia</jtitle><date>2023-12</date><risdate>2023</risdate><volume>19</volume><issue>S10</issue><epage>n/a</epage><issn>1552-5260</issn><eissn>1552-5279</eissn><abstract><![CDATA[Background
The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.
Method
We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.
Result
Higher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p<0.001) and higher P‐tau181 (ß = 0.21; p<0.001). Aß1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2). We found stronger association between Aß1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes. Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aß1‐42 (indirect effect: ß = ‐0.03; p<0.001). Aß1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aß1‐42 on P‐tau181 levels (ß = ‐0.14; p<0.001) and HCV (ß = 0.06; p<0.05), and of P‐tau181 levels onto HCV (ß = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: ß = 0.36; p < 0.05) and HCV (indirect effect: ß = ‐0.24; p < 0.05) through Aß1‐42 was observed.
Conclusion
Expression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.]]></abstract><doi>10.1002/alz.081655</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| title | Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort |
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