The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease
CSF concentrations of β-amyloid 42 (Aβ42) and phosphorylated tau (p-tau) are well-established biomarkers of Alzheimer's disease and have been studied in relation to several neuropathological features both in patients and in cognitively unimpaired individuals. The CSF p-tau/Aβ42 ratio, a biomark...
| Autores: | , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/71640 |
| Acceso en línea: | http://hdl.handle.net/10230/71640 http://dx.doi.org/10.1093/braincomms/fcae451 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer's disease CSF biomarkers Amyloid deposition Brain structure p-tau/Aß42 ratio |
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The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease |
| title |
The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease |
| spellingShingle |
The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease Cacciaglia, Raffaele Alzheimer's disease CSF biomarkers Amyloid deposition Brain structure p-tau/Aß42 ratio |
| title_short |
The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease |
| title_full |
The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease |
| title_fullStr |
The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease |
| title_full_unstemmed |
The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease |
| title_sort |
The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease |
| dc.creator.none.fl_str_mv |
Cacciaglia, Raffaele Shekari, Mahnaz Salvadó, Gemma Milà Alomà, Marta Falcón, Carles Sánchez Benavides, Gonzalo Minguillón, Carolina Fauria, Karine Grau-Rivera, Oriol Molinuevo, José Luis Blennow, Kaj Zetterberg, Henrik Quevenco, Frances-Catherine Suárez-Calvet, Marc Gispert López, Juan Domingo ALFA Study |
| author |
Cacciaglia, Raffaele |
| author_facet |
Cacciaglia, Raffaele Shekari, Mahnaz Salvadó, Gemma Milà Alomà, Marta Falcón, Carles Sánchez Benavides, Gonzalo Minguillón, Carolina Fauria, Karine Grau-Rivera, Oriol Molinuevo, José Luis Blennow, Kaj Zetterberg, Henrik Quevenco, Frances-Catherine Suárez-Calvet, Marc Gispert López, Juan Domingo ALFA Study |
| author_role |
author |
| author2 |
Shekari, Mahnaz Salvadó, Gemma Milà Alomà, Marta Falcón, Carles Sánchez Benavides, Gonzalo Minguillón, Carolina Fauria, Karine Grau-Rivera, Oriol Molinuevo, José Luis Blennow, Kaj Zetterberg, Henrik Quevenco, Frances-Catherine Suárez-Calvet, Marc Gispert López, Juan Domingo ALFA Study |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Alzheimer's disease CSF biomarkers Amyloid deposition Brain structure p-tau/Aß42 ratio |
| topic |
Alzheimer's disease CSF biomarkers Amyloid deposition Brain structure p-tau/Aß42 ratio |
| description |
CSF concentrations of β-amyloid 42 (Aβ42) and phosphorylated tau (p-tau) are well-established biomarkers of Alzheimer's disease and have been studied in relation to several neuropathological features both in patients and in cognitively unimpaired individuals. The CSF p-tau/Aβ42 ratio, a biomarker combining information from both pathophysiological processes, has emerged as a promising tool for monitoring disease progression, even at pre-clinical stages. Here, we studied the association between the CSF p-tau/Aβ42 ratio with downstream markers of pre-clinical Alzheimer's disease progression including brain structure, glucose metabolism, fibrillary Aβ deposition and cognitive performance in 234 cognitively unimpaired individuals, who underwent cognitive testing, a lumbar puncture, MRI, 18F-fluorodeoxyglucose and 18F-flutemetamol PET scanning. We evaluated both main effects and interactions with Alzheimer's disease risk factors, such as older age, female sex and the apoliporoptein E (APOE)-ɛ4 allele, in a priori defined regions of interest and further examined the associations on the whole-brain using voxel-wise regressions. In addition, as the association between CSF Alzheimer's disease biomarkers and brain structure and function may be non-linear, we tested the interaction between the CSF p-tau/Aβ42 ratio and stages of pre-clinical Alzheimer's disease defined using the amyloid (A) and tau (T) classification. We found significantly positive associations between CSF p-tau/Aβ42 and both cortical Aβ deposition and regional grey matter volume while no effect was observed for brain metabolism. A significant interaction with age indicated that, for the same level of CSF p-tau/Aβ42, older individuals displayed both increased Aβ deposition and lower grey matter volume, in widespread cortical areas. In addition, we found that women compared with men had a greater Aβ fibrillary accumulation in midline cortical areas and inferior temporal regions, for the same level of the CSF biomarker. The impact of CSF p-tau/Aβ42 on grey matter volume was modulated by AT stages, with A+T+ individuals displaying significantly less positive associations in areas of early atrophy in the Alzheimer's continuum. Finally, we found that sex and APOE-ɛ4 modulated the association between the CSF biomarker and episodic memory as well as abstract reasoning, respectively. Our data indicate that the CSF p-tau/Aβ42 ratio is strongly associated with multiple downstream neuropathological events in cognitively unimpaired individuals and may thus serve as a potent biomarker to investigate the earliest changes in pre-clinical Alzheimer's disease. Given that its impact on both Aβ deposition and grey matter volume is modulated by specific risk factors, our results highlight the need to take into account such predisposing variables in both clinical practice and prevention trials. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024 2025 2025 2025 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/71640 http://dx.doi.org/10.1093/braincomms/fcae451 http://hdl.handle.net/10230/71640 |
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http://hdl.handle.net/10230/71640 http://dx.doi.org/10.1093/braincomms/fcae451 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
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Brain Communications. 2024;7(1) info:eu-repo/grantAgreement/ES/3PE/PID2021-125433OA-100 info:eu-repo/grantAgreement/EC/HE/101053962 info:eu-repo/grantAgreement/EC/H2020/860197 info:eu-repo/grantAgreement/EC/H2020/948677 info:eu-repo/grantAgreement/EC/H2020/847648 |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf application/pdf |
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Oxford University Press |
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Oxford University Press |
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reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's diseaseCacciaglia, RaffaeleShekari, MahnazSalvadó, GemmaMilà Alomà, MartaFalcón, CarlesSánchez Benavides, GonzaloMinguillón, CarolinaFauria, KarineGrau-Rivera, OriolMolinuevo, José LuisBlennow, KajZetterberg, HenrikQuevenco, Frances-CatherineSuárez-Calvet, MarcGispert López, Juan DomingoALFA StudyAlzheimer's diseaseCSF biomarkersAmyloid depositionBrain structurep-tau/Aß42 ratioCSF concentrations of β-amyloid 42 (Aβ42) and phosphorylated tau (p-tau) are well-established biomarkers of Alzheimer's disease and have been studied in relation to several neuropathological features both in patients and in cognitively unimpaired individuals. The CSF p-tau/Aβ42 ratio, a biomarker combining information from both pathophysiological processes, has emerged as a promising tool for monitoring disease progression, even at pre-clinical stages. Here, we studied the association between the CSF p-tau/Aβ42 ratio with downstream markers of pre-clinical Alzheimer's disease progression including brain structure, glucose metabolism, fibrillary Aβ deposition and cognitive performance in 234 cognitively unimpaired individuals, who underwent cognitive testing, a lumbar puncture, MRI, 18F-fluorodeoxyglucose and 18F-flutemetamol PET scanning. We evaluated both main effects and interactions with Alzheimer's disease risk factors, such as older age, female sex and the apoliporoptein E (APOE)-ɛ4 allele, in a priori defined regions of interest and further examined the associations on the whole-brain using voxel-wise regressions. In addition, as the association between CSF Alzheimer's disease biomarkers and brain structure and function may be non-linear, we tested the interaction between the CSF p-tau/Aβ42 ratio and stages of pre-clinical Alzheimer's disease defined using the amyloid (A) and tau (T) classification. We found significantly positive associations between CSF p-tau/Aβ42 and both cortical Aβ deposition and regional grey matter volume while no effect was observed for brain metabolism. A significant interaction with age indicated that, for the same level of CSF p-tau/Aβ42, older individuals displayed both increased Aβ deposition and lower grey matter volume, in widespread cortical areas. In addition, we found that women compared with men had a greater Aβ fibrillary accumulation in midline cortical areas and inferior temporal regions, for the same level of the CSF biomarker. The impact of CSF p-tau/Aβ42 on grey matter volume was modulated by AT stages, with A+T+ individuals displaying significantly less positive associations in areas of early atrophy in the Alzheimer's continuum. Finally, we found that sex and APOE-ɛ4 modulated the association between the CSF biomarker and episodic memory as well as abstract reasoning, respectively. Our data indicate that the CSF p-tau/Aβ42 ratio is strongly associated with multiple downstream neuropathological events in cognitively unimpaired individuals and may thus serve as a potent biomarker to investigate the earliest changes in pre-clinical Alzheimer's disease. Given that its impact on both Aβ deposition and grey matter volume is modulated by specific risk factors, our results highlight the need to take into account such predisposing variables in both clinical practice and prevention trials.The research leading to these results has received funding from ‘la Caixa’ Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2021 SGR 00913. R.C. receives funding from ‘Ministerio de Ciencia, Innovación y Universidades—Agencia Estatal de Investigación’ MCIN/AEI/10.13039/501100011033/FEDER, EU, through project PID2021-125433OA-100 and support from grant RYC2021-031128-I, funded by MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/Plan de Recuperación, Transformación y Resiliencia (PRTR). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Union’s Horizon Europe research and innovation programme under grant agreement no. 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694) and the UK Dementia Research Institute at University College London (UCL) (UKDRI-1003). K.B. is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the Avtal om Läkarutbildning och Forskning (ALF) agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Programme for Neurodegenerative Disorders (JPND2019-466-236), the National Institutes of Health (NIH), USA, (grant #1R01AG068398-01), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495) and the Alzheimer’s Association 2022–25 Grant (SG-23-1038904 QC). M.S.-C. receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 948677), Project ‘PI19/00155’, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union and from a fellowship from ‘la Caixa’ Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 847648 (LCF/BQ/PR21/11840004). O.G.-R. is supported by the ‘Ministerio de Ciencia, Innovación y Universidades' (IJC2020-043417-I) and receives funding from the Alzheimer’s Association (2019-AARF-644568) and the Instituto de Salud Carlos III (PI19/00117).Oxford University Press2025202520242025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/71640http://dx.doi.org/10.1093/braincomms/fcae451http://hdl.handle.net/10230/71640reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésBrain Communications. 2024;7(1)info:eu-repo/grantAgreement/ES/3PE/PID2021-125433OA-100info:eu-repo/grantAgreement/EC/HE/101053962info:eu-repo/grantAgreement/EC/H2020/860197info:eu-repo/grantAgreement/EC/H2020/948677info:eu-repo/grantAgreement/EC/H2020/847648© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/716402026-05-29T05:05:01Z |
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15,81155 |