Anna L Svenningsson, Diana I Bocancea, Erik Stomrud, Anita van Loenhoud, Frederik Barkhof, Niklas Mattsson-Carlgren, Sebastian Palmqvist, Oskar Hansson, Rik Ossenkoppele
{"title":"Biological mechanisms of resilience to tau pathology in Alzheimer's disease.","authors":"Anna L Svenningsson, Diana I Bocancea, Erik Stomrud, Anita van Loenhoud, Frederik Barkhof, Niklas Mattsson-Carlgren, Sebastian Palmqvist, Oskar Hansson, Rik Ossenkoppele","doi":"10.1186/s13195-024-01591-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>In Alzheimer's disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience).</p><p><strong>Methods: </strong>We included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline.</p><p><strong>Results: </strong>Regarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (β<sub>interaction</sub> = -0.009, p<sub>FDR</sub> = 0.047) and VEGF-B (β<sub>interaction</sub> = -0.010, p<sub>FDR</sub> = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, p<sub>FDR</sub> = 0.033) and lower baseline cortical thickness (β = -0.708, p<sub>FDR</sub> = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; β<sub>interaction</sub> -0.073--0.069, p<sub>FDR</sub> 0.001-0.045), vascular (VEGF-A, VEGF-D, PGF; β<sub>interaction</sub> -0.099--0.063, p<sub>FDR</sub> < 0.001-0.046), synaptic (14-3-3ζ/δ; β<sub>interaction</sub> = -0.092, p<sub>FDR</sub> = 0.041), axonal (NfL; β<sub>interaction</sub> = -0.079, p<sub>FDR</sub> < 0.001), and neurotrophic (NGF; β<sub>interaction</sub> = 0.091, p<sub>FDR</sub> < 0.001) biomarkers. In MCI higher NfL levels (β<sub>main</sub> = -0.690, p<sub>FDR</sub> = 0.025) were associated with faster cognitive decline independent of tau-PET signal.</p><p><strong>Conclusions: </strong>Biomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9000,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470552/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's Research & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13195-024-01591-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: In Alzheimer's disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience).
Methods: We included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline.
Results: Regarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073--0.069, pFDR 0.001-0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099--0.063, pFDR < 0.001-0.046), synaptic (14-3-3ζ/δ; βinteraction = -0.092, pFDR = 0.041), axonal (NfL; βinteraction = -0.079, pFDR < 0.001), and neurotrophic (NGF; βinteraction = 0.091, pFDR < 0.001) biomarkers. In MCI higher NfL levels (βmain = -0.690, pFDR = 0.025) were associated with faster cognitive decline independent of tau-PET signal.
Conclusions: Biomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience.
期刊介绍：
Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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