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Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.ORCID iD: 0000-0002-1812-3581
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.ORCID iD: 0000-0002-8114-7615
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2021 (English)In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 13, article id 130Article in journal (Refereed) Published
Abstract [en]

Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer’s disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.

Methods: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.

Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1–24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404–7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947–2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.

Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2021. Vol. 13, article id 130
Keywords [en]
Leukocyte telomere length, Dementia, Risk factors, Time-to-event analysis, Competing risks, Vascular dementia, Death
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-186769DOI: 10.1186/s13195-021-00871-yISI: 000673978800001PubMedID: 34266503Scopus ID: 2-s2.0-85110170246OAI: oai:DiVA.org:umu-186769DiVA, id: diva2:1586489
Note

Correction: Hackenhaar, F.S., Josefsson, M., Adolfsson, A.N. et al. Correction: Short leukocyte telomeres predict 25-year Alzheimer’s disease incidence in non-APOE ε4-carriers. Alz Res Therapy 16, 39 (2024). DOI: 10.1186/s13195-024-01388-w

Available from: 2021-08-20 Created: 2021-08-20 Last updated: 2024-04-08Bibliographically approved

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Schäfer Hackenhaar, FernandaJosefsson, MariaNordin Adolfsson, AnnelieLandfors, MattiasKauppi, KarolinaHultdin, MagnusAdolfsson, RolfDegerman, SofiePudas, Sara

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Schäfer Hackenhaar, FernandaJosefsson, MariaNordin Adolfsson, AnnelieLandfors, MattiasKauppi, KarolinaHultdin, MagnusAdolfsson, RolfDegerman, SofiePudas, Sara
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Department of Integrative Medical Biology (IMB)Umeå Centre for Functional Brain Imaging (UFBI)Centre for Demographic and Ageing Research (CEDAR)StatisticsPsychiatryPathologyDepartment of Clinical Microbiology
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