Biological mechanisms of resilience to tau pathology in Alzheimer’s disease

Svenningsson, Anna L.; Bocancea, Diana I.; Stomrud, Erik; van Loenhoud, Anita; Barkhof, Frederik; Mattsson-Carlgren, Niklas; Palmqvist, Sebastian; Hansson, Oskar; Ossenkoppele, Rik

Biological mechanisms of resilience to tau pathology in Alzheimer’s disease

Mark

Svenningsson, Anna L. ^LU

; Bocancea, Diana I. ^LU ; Stomrud, Erik ^LU

; van Loenhoud, Anita ; Barkhof, Frederik ; Mattsson-Carlgren, Niklas ^LU

; Palmqvist, Sebastian ^LU

; Hansson, Oskar ^LU

and Ossenkoppele, Rik ^LU (2024) In Alzheimer's Research and Therapy 16(1).

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... (More); 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 (β_interaction = -0.009, p_FDR = 0.047) and VEGF-B (β_interaction = -0.010, p_FDR = 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_FDR = 0.033) and lower baseline cortical thickness (β = -0.708, p_FDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; β_interaction -0.073–-0.069, p_FDR 0.001–0.045), vascular (VEGF-A, VEGF-D, PGF; β_interaction -0.099–-0.063, p_FDR < 0.001–0.046), synaptic (14–3-3ζ/δ; β_interaction = -0.092, p_FDR = 0.041), axonal (NfL; β_interaction = -0.079, p_FDR < 0.001), and neurotrophic (NGF; β_interaction = 0.091, p_FDR < 0.001) biomarkers. In MCI higher NfL levels (β_main = -0.690, p_FDR = 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.
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Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/b061b061-deed-494a-9149-903122c9e9bc

author

Svenningsson, Anna L. ^LU

; Bocancea, Diana I. ^LU ; Stomrud, Erik ^LU

; van Loenhoud, Anita ; Barkhof, Frederik ; Mattsson-Carlgren, Niklas ^LU

; Palmqvist, Sebastian ^LU

; Hansson, Oskar ^LU

and Ossenkoppele, Rik ^LU

organization

publishing date

2024-12

type

Contribution to journal

publication status

published

subject

Neurosciences

keywords

Alzheimer’s disease, Brain resilience, Cognitive resilience, Tau

in

Alzheimer's Research and Therapy

volume

16

issue

1

article number

221

publisher

BioMed Central (BMC)

external identifiers

scopus:85206122849
pmid:39396028

ISSN

1758-9193

DOI

10.1186/s13195-024-01591-9

language

English

LU publication?

yes

id

b061b061-deed-494a-9149-903122c9e9bc

date added to LUP

2024-11-27 15:28:21

date last changed

2025-07-10 10:10:59

@article{b061b061-deed-494a-9149-903122c9e9bc,
  abstract     = {{<p>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 (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> &lt; 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> &lt; 0.001), and neurotrophic (NGF; β<sub>interaction</sub> = 0.091, p<sub>FDR</sub> &lt; 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. 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.</p>}},
  author       = {{Svenningsson, Anna L. and Bocancea, Diana I. and Stomrud, Erik and van Loenhoud, Anita and Barkhof, Frederik and Mattsson-Carlgren, Niklas and Palmqvist, Sebastian and Hansson, Oskar and Ossenkoppele, Rik}},
  issn         = {{1758-9193}},
  keywords     = {{Alzheimer’s disease; Brain resilience; Cognitive resilience; Tau}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Alzheimer's Research and Therapy}},
  title        = {{Biological mechanisms of resilience to tau pathology in Alzheimer’s disease}},
  url          = {{http://dx.doi.org/10.1186/s13195-024-01591-9}},
  doi          = {{10.1186/s13195-024-01591-9}},
  volume       = {{16}},
  year         = {{2024}},
}

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Biological mechanisms of resilience to tau pathology in Alzheimer’s disease