. 2025 Sep:119:105886.

doi: 10.1016/j.ebiom.2025.105886. Epub 2025 Aug 19.

Longitudinal association of shorter leukocyte telomere length with CSF biomarker dynamics across early Alzheimer's disease stages in at-risk individuals

Blanca Rodríguez-Fernández¹, Armand González-Escalante², Patricia Genius³, Tavia E Evans⁴, Paula Ortiz-Romero⁵, Carolina Minguillón⁶, Gwendlyn Kollmorgen⁷, Nicholas J Ashton⁸, Henrik Zetterberg⁹, Kaj Blennow¹⁰, Juan Domingo Gispert¹¹, Arcadi Navarro¹², Marc Suárez-Calvet¹³, Aleix Sala-Vila¹⁴, Marta Crous-Bou¹⁵, Natàlia Vilor-Tejedor¹⁶; ALFA Study

Collaborators, Affiliations

Collaborators

ALFA Study:
Müge Akinci, Federica Anastasi, Annabella Beteta, Raffaele Cacciaglia, Lidia Canals-Gispert, Alba Cañas-Martínez, Carme Deulofeu, Maria Emilio, Irene Cumplido-Mayoral, Marta Del Campo, Sherezade Fuentes, Laura Hernández, Gema Huesa, Jordi Huguet, Esther Jiménez, David López-Martos, Paula Marne, Eleni Palpatzis, Wiesje Pelkmans, Albina Polo, Sandra Pradas, Mahnaz Shekari, Lluís Solsona, Anna Soteras, Núria Tort-Colet, Marc Vilanova, Anna Brugulat-Serrat, Gonzalo Sánchez Benavides, Marta Milà Alomà, David Vállez-García, Gemma Salvadò, Eider Arenaza Urquijo, Oriol Grau Rivera, Karine Fauria, Ana Fernández-Arcos, Laura Stankeviciute, Michalis Kassinopoulos, Anna Coward, Clàudia Porta, Clara Gallay, Aldana Lizarraga, Felipe Hernández Villamizar, Isabel Pérez-Gutiérrez, Noelia Giselle Rugna, Ricardo Aquite Aguilar

Affiliations

¹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Universitat Autònoma de Barcelona (UAB), Plaça Cívica, Bellaterra (Cerdanyola del Vallès), Barcelona, 08193, Spain. Electronic address: brodriguez@barcelonabeta.org.
² Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Universitat Pompeu Fabra (UPF), 10-12 Plaça de la Mercè, Barcelona, 08002, Spain.
³ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain.
⁴ Department of Human Genetics, Radboud University Medical Center, 10 Geert Grooteplein-Zuid, Nijmegen, 6525GA, Netherlands.
⁵ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain.
⁶ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBER-FES), Instituto de Salud Carlos III, 5 Avenida de Monforte de Lemos, Madrid, 28029, Spain.
⁷ Roche Diagnostics GmbH, 2 Nonnenwald, Penzberg, 82377, Germany.
⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, S-431 80, Sweden; Wallenberg Centre for Molecular Medicine, University of Gothenburg, Gothenburg, S-413 45, Sweden; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, SE5 9RT, United Kingdom; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, SE5 8AF, United Kingdom.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, S-431 80, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 6BG, United Kingdom; UK Dementia Research Institute at UCL, London, WC1N 6BG, United Kingdom; Hong Kong Center for Neurodegenerative Diseases, Units 1501-1502, 1512-1518, 15/F Building 17W, 17 Science Park West Avenue, Science Park, Clear Water Bay, Hong Kong; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53792, USA; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 31 Göteborgsvägen, Mölndal, S-431 80, Sweden.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 31 Göteborgsvägen, Mölndal, S-431 80, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, 405 30, Sweden; Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, Sorbonne University, 47 Boulevard de l'Hôpital, Paris, 75013, France; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, 96 Jinzhai Road, East Campus, Hefei, Anhui, 230026, China.
¹¹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain.
¹² Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 23 Passeig Lluís Companys, Barcelona, 08010, Spain; Department of Experimental and Health Sciences, Institute of Evolutionary Biology (CSIC-UPF), 37 Passeig Marítim de la Barceloneta, Ciutat Vella, Barcelona, 08003, Spain.
¹³ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Servei de Neurologia, Hospital del Mar, 25-29 Passeig Marítim, Barcelona, 08003, Spain.
¹⁴ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 3-5 Avenida de Monforte de Lemos, Madrid, 28029, Spain; Fatty Acid Research Institute, Sioux Falls, SD, 57105, USA.
¹⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, School of Public Health 2, 677 Huntington Avenue, Boston, MA, 02115, USA; Catalan Institute of Oncology (ICO)-Bellvitge Biomedical Research Center (IDIBELL), Hospital Duran i Reynals, 199 Avinguda de la Granvia de l'Hospitalet, L'Hospitalet de Llobregat, Barcelona, 08908, Spain.
¹⁶ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Department of Human Genetics, Radboud University Medical Center, 10 Geert Grooteplein-Zuid, Nijmegen, 6525GA, Netherlands. Electronic address: nvilor@barcelonabeta.org.

PMID: 40834628
PMCID: PMC12395440
DOI: 10.1016/j.ebiom.2025.105886

Longitudinal association of shorter leukocyte telomere length with CSF biomarker dynamics across early Alzheimer's disease stages in at-risk individuals

Blanca Rodríguez-Fernández et al. EBioMedicine. 2025 Sep.

. 2025 Sep:119:105886.

doi: 10.1016/j.ebiom.2025.105886. Epub 2025 Aug 19.

Authors

Collaborators

ALFA Study:
Müge Akinci, Federica Anastasi, Annabella Beteta, Raffaele Cacciaglia, Lidia Canals-Gispert, Alba Cañas-Martínez, Carme Deulofeu, Maria Emilio, Irene Cumplido-Mayoral, Marta Del Campo, Sherezade Fuentes, Laura Hernández, Gema Huesa, Jordi Huguet, Esther Jiménez, David López-Martos, Paula Marne, Eleni Palpatzis, Wiesje Pelkmans, Albina Polo, Sandra Pradas, Mahnaz Shekari, Lluís Solsona, Anna Soteras, Núria Tort-Colet, Marc Vilanova, Anna Brugulat-Serrat, Gonzalo Sánchez Benavides, Marta Milà Alomà, David Vállez-García, Gemma Salvadò, Eider Arenaza Urquijo, Oriol Grau Rivera, Karine Fauria, Ana Fernández-Arcos, Laura Stankeviciute, Michalis Kassinopoulos, Anna Coward, Clàudia Porta, Clara Gallay, Aldana Lizarraga, Felipe Hernández Villamizar, Isabel Pérez-Gutiérrez, Noelia Giselle Rugna, Ricardo Aquite Aguilar

Affiliations

¹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Universitat Autònoma de Barcelona (UAB), Plaça Cívica, Bellaterra (Cerdanyola del Vallès), Barcelona, 08193, Spain. Electronic address: brodriguez@barcelonabeta.org.
² Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Universitat Pompeu Fabra (UPF), 10-12 Plaça de la Mercè, Barcelona, 08002, Spain.
³ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain.
⁴ Department of Human Genetics, Radboud University Medical Center, 10 Geert Grooteplein-Zuid, Nijmegen, 6525GA, Netherlands.
⁵ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain.
⁶ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBER-FES), Instituto de Salud Carlos III, 5 Avenida de Monforte de Lemos, Madrid, 28029, Spain.
⁷ Roche Diagnostics GmbH, 2 Nonnenwald, Penzberg, 82377, Germany.
⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, S-431 80, Sweden; Wallenberg Centre for Molecular Medicine, University of Gothenburg, Gothenburg, S-413 45, Sweden; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, SE5 9RT, United Kingdom; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, SE5 8AF, United Kingdom.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, S-431 80, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 6BG, United Kingdom; UK Dementia Research Institute at UCL, London, WC1N 6BG, United Kingdom; Hong Kong Center for Neurodegenerative Diseases, Units 1501-1502, 1512-1518, 15/F Building 17W, 17 Science Park West Avenue, Science Park, Clear Water Bay, Hong Kong; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53792, USA; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 31 Göteborgsvägen, Mölndal, S-431 80, Sweden.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 31 Göteborgsvägen, Mölndal, S-431 80, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, 405 30, Sweden; Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, Sorbonne University, 47 Boulevard de l'Hôpital, Paris, 75013, France; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, 96 Jinzhai Road, East Campus, Hefei, Anhui, 230026, China.
¹¹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain.
¹² Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 23 Passeig Lluís Companys, Barcelona, 08010, Spain; Department of Experimental and Health Sciences, Institute of Evolutionary Biology (CSIC-UPF), 37 Passeig Marítim de la Barceloneta, Ciutat Vella, Barcelona, 08003, Spain.
¹³ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Servei de Neurologia, Hospital del Mar, 25-29 Passeig Marítim, Barcelona, 08003, Spain.
¹⁴ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 3-5 Avenida de Monforte de Lemos, Madrid, 28029, Spain; Fatty Acid Research Institute, Sioux Falls, SD, 57105, USA.
¹⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, School of Public Health 2, 677 Huntington Avenue, Boston, MA, 02115, USA; Catalan Institute of Oncology (ICO)-Bellvitge Biomedical Research Center (IDIBELL), Hospital Duran i Reynals, 199 Avinguda de la Granvia de l'Hospitalet, L'Hospitalet de Llobregat, Barcelona, 08908, Spain.
¹⁶ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Department of Human Genetics, Radboud University Medical Center, 10 Geert Grooteplein-Zuid, Nijmegen, 6525GA, Netherlands. Electronic address: nvilor@barcelonabeta.org.

PMID: 40834628
PMCID: PMC12395440
DOI: 10.1016/j.ebiom.2025.105886

Abstract

Background: Short telomere length (TL), a hallmark of biological ageing, has been associated with an increased risk of Alzheimer's disease (AD), but its pathophysiological role remains unclear. This study explored the relationship between blood leukocyte TL (LTL), cerebrospinal fluid (CSF) AD biomarkers changes, and brain structure across early stages of the AD continuum.

Methods: We included 346 cognitively unimpaired participants (aged 49-71) from the ALFA cohort, enriched for AD risk (53.2% APOE-ε4 carriers; 34% amyloid-positive). LTL was measured at baseline (visit 0) using quantitative PCR. Associations were assessed between baseline LTL and CSF biomarkers at visit 1 (mean follow-up from baseline = 3.98 years, SD = 1.02), and with changes in CSF biomarkers between visits 1 and 2 (mean interval = 3.45 years, SD = 0.58). Cortical thickness in ageing- and AD-vulnerable brain regions was evaluated by magnetic resonance imaging (MRI) at visit 1. Analyses were stratified by APOE-ε4 status and amyloid-tau (AT) profiles. Mediation models tested whether CSF biomarkers mediated LTL-cortical thickness associations.

Findings: Shorter LTL was associated with higher astrocytic reactivity at visit 1 and with increased synaptic dysfunction over time. Among APOE-ε4 carriers and AT-positive individuals, shorter LTL was associated with higher p-tau181 and neurodegeneration markers. Shorter LTL was associated with greater cortical thickness in ageing- and AD-vulnerable regions, partially mediated by astrocytic reactivity biomarkers.

Interpretation: These findings suggest that shorter telomeres are associated with early AD-related biological changes, potentially via mechanisms involving astrocytic reactivity and brain structural alterations. LTL may serve as an early marker of vulnerability to neurodegenerative processes in at-risk populations.

Funding: AARG-19-618265; PI19/00119; LCF/PR/GN17/10300004; TriBEKa-17-519007; # SLT002/16/00201.

Keywords: Alzheimer's disease; Cortical thickness; Glial biomarkers; Leukocyte telomere length; Preclinical.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests BR-F, AG-E, TEE, MS-C, PO-R, NA, AN, and AS-V have nothing to disclose. GK is a full-time employee of Roche Diagnostics GmbH. CM has received research funding from an EU-FINGERS JPND research grant and from an ADDF digital biomarkers research grant; both paid to the institution. JDG receives research funding from Roche Diagnostics, Hoffmann-La Roche, GE Healthcare, the Innovative Health Initiative (IHI) of the European Commission (Grant agreement No. 101112145), BrightFocus Foundation (A2022034S), Instituto de Salud Carlos III (PMP22/00022), and Fundació La Marató de TV3 (202318-30-31-32). He has given lectures in symposia sponsored by Biogen, Philips, and Life-MI; received consulting fees from Roche Diagnostics; and serves on a scientific advisory board at Prothena Biosciences. HZ has served on scientific advisory boards and/or as a consultant for: Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave. He has given lectures sponsored by: Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is part of the GU Ventures Incubator Program (outside the submitted work). He is supported by the Swedish Research Council (#2023-00356, #2022-01018, and #2019-02397); the European Union's Horizon Europe research and innovation programme (grant agreement No. 101053962); Swedish State Support for Clinical Research (#ALFGBG-71320); 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, #ADSF-21-831377-C, and #ADSF-24-1284328-C); the European Partnership on Metrology (NEuroBioStand, #22HLT07); the Bluefield Project; Cure Alzheimer's Fund; the Olav Thon Foundation; the Erling-Persson Family Foundation; Familjen Rönströms Stiftelse; 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); the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre; and the UK Dementia Research Institute at UCL (UKDRI-1003). KB has served as a consultant, on advisory boards, or on data monitoring committees for: Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers. He is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), part of the GU Ventures Incubator Program. He is supported by the Swedish Research Council (#201700915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB2018092016615); the Swedish Alzheimer Foundation (#AF742881); Hjärnfonden, Sweden (#FO20170243); the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (#ALFGBG715986); the European Union Joint Program for Neurodegenerative Disorders (JPND2019466236); the National Institutes of Health (NIH), USA (grant #1R01AG06839801); and the Alzheimer's Association 2021 Zenith Award (ZEN21848495). MS-C has received in the past 36 months consultancy/speaker fees (paid to the institution) from Almirall, Eli Lilly, Novo Nordisk, and Roche Diagnostics. He has received consultancy fees or served on advisory boards (paid to the institution) for Eli Lilly, Grifols, and Roche Diagnostics. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from: ADx Neurosciences, Alamar Biosciences, ALZPath, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development, Meso Scale Discovery, and Roche Diagnostics. MS-C did not receive any personal compensation from these organisations or any other for-profit organisation. MS-C receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 948677); the Instituto de Salud Carlos III (ISCIII) through projects PI19/00155 and PI22/00456 (co-funded by European Regional Development Fund (FEDER) “A way to make Europe”) and receives support from a fellowship funded by “la Caixa” Foundation (ID 100010434), and the Marie Skłodowska-Curie grant agreement No. 847648 (fellowship code LCF/BQ/PR21/11840004). MC-B receives funding from the Alzheimer's Association International (Grant AARG-19–618265); and the Spanish Ministry of Health. NV-T has received funding from the Juan de la Cierva Incorporación program (IJDC2020-043216-I) and Ramón y Cajal (RYC2022-038136-I) programmes, funded by the Ministerio de Ciencia, Innovación y Universidades–Spanish State Research Agency (MCIN/AEI/10.13039/501100011033), co-funded by the European Union “Next GenerationEU”/PRTR, and project PID2022-143106OA-I00 (co-funded by the European Union FEDER). She receives additional funding from the Alzheimer's Disease Data Initiative (ADDI) through the William H. Gates Sr. Fellowship Program, from the Ajuntament de Barcelona and “la Caixa” Foundation (project 23S06083-001), and from Alzheimer Nederland (InterAct-beurs ′24, #WE.08-2024-07). BR-F and PG have received honoraria for lectures from the University of Vic-Central University of Catalonia, and travel support from the Alzheimer's Association International. NV-T has received honoraria for lectures from the University of Vic-Central University of Catalonia, the University of Valencia, and UNED. She has also received travel support from ADDI, Alzheimer Nederland, and the Alzheimer's Association International. She serves as scientific co-director of the PRISMA association and is on the board committee of the Spanish Biostatistics Society.

Figures

**Fig. 1**
**Flowchart of participant selection and dataset construction**. From 1520 cognitively unimpaired individuals with baseline LTL data (ALFA parent, visit 0, 2013–2014), three nested datasets were derived after quality control: (1) CSF V1 (N = 346), with CSF biomarkers at visit 1 (2016–2019) and LTL data at visit 0; (2) MRI V1 (N = 325), with CSF and MRI data at visit 1, and LTL data at visit 0; and (3) CSF longitudinal (N = 237), with CSF data at both visit 1 and visit 2 (2019–2022) and LTL data at visit 0. ¹Detailed quality control of LTL measurements can be found in Rodríguez-Fernández et al., 2024. ²LTL outliers were removed once merged with CSF data.

**Fig. 2**
**Significant associations between LTL and CSF biomarkers at visit 1 in the global sample**. Scatter plot representing the linear association between LTL and log-transformed (a) CSF GFAP and (b) CSF S100B at visit 1 in the global sample (N = 346). Standardised regression coefficients (β) and P values (unadjusted; FDR-corrected values are provided in Supplementary Table S5) were calculated using a linear model adjusted for age, sex, and APOE-ε4 status.

**Fig. 3**
**Significant longitudinal association between LTL and change in CSF biomarkers over time**. Scatter plot representing the linear association between LTL and the change in log-transformed CSF α-synuclein over a mean follow-up period of 3.45 (SD = 0.58) years (N = 237). Standardised regression coefficients (β) and P values (unadjusted; FDR-corrected values are provided in Supplementary Table S5) were calculated using a linear model adjusted for age, sex, APOE-ε4 status, time difference between lumbar punctures, and CSF α-synuclein at visit 1.

**Fig. 4**
**Forest plot illustrating the associations between LTL and CSF biomarkers at visit 1 and their longitudinal changes. Results are presented for the full sample and stratified by *APOE*-ε4 and AT status**. Each point represents the standardised coefficient for one association model, horizontal lines represent the 95% confidence intervals and colours represent the biomarker family for multiple comparison correction. Standardised regression coefficients (β) and P values were calculated using linear models for CSF biomarkers at visit 1 adjusted for age, sex, and *APOE*-ε4 status, while longitudinal models were further adjusted for time between lumbar punctures and CSF biomarker levels at visit 1.

**Fig. 5**
**Associations between LTL and cortical thickness in AD- and ageing-vulnerable regions**. Scatter plot representing the linear association between LTL and (a) AD cortical thickness signature and (b) ageing cortical thickness signature. (c) Schema representing linear structural modelling results evaluating the mediator role of (c) CSF GFAP and (d) CSF YKL-40 on the association between LTL and AD cortical thickness signatures (N = 325). Models were corrected for age, sex, *APOE*-ε4 status, and firmware MRI version. All coefficients were standardised. AD signature represents average cortical thickness in entorhinal, inferior temporal, middle temporal, and fusiform. Ageing signature represents average cortical thickness in calcarine, caudal insula, cuneus, caudal fusiform, dorsomedial frontal, lateral occipital, precentral, and inferior frontal.

See this image and copyright information in PMC

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Longitudinal association of shorter leukocyte telomere length with CSF biomarker dynamics across early Alzheimer's disease stages in at-risk individuals

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Affiliations

Longitudinal association of shorter leukocyte telomere length with CSF biomarker dynamics across early Alzheimer's disease stages in at-risk individuals

Authors

Collaborators

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Abstract

Conflict of interest statement

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