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Interactions between vascular burden and amyloid-β pathology on trajectories of tau accumulation

Coomans, Emma M. LU ; van Westen, Danielle LU orcid ; Binette, Alexa Pichet LU ; Strandberg, Olof LU ; Spotorno, Nicola LU ; Serrano, Geidy E. ; Beach, Thomas G. ; Palmqvist, Sebastian LU orcid ; Stomrud, Erik LU orcid and Ossenkoppele, Rik LU , et al. (2024) In Brain 147(3). p.949-960
Abstract

Cerebrovascular pathology often co-exists with Alzheimer’s disease pathology and can contribute to Alzheimer’s disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer’s disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0... (More)

Cerebrovascular pathology often co-exists with Alzheimer’s disease pathology and can contribute to Alzheimer’s disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer’s disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ε4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ε4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P < 0.001) and longitudinal tau accumulation (β = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = −0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P < 0.001) and between infarcts and plaque density (β = −0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology—in the presence of amyloid-β pathology—modifies tau accumulation in early stages of Alzheimer’s disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer’s disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, amyloid-β, tau, vascular burden, vascular risk
in
Brain
volume
147
issue
3
pages
12 pages
publisher
Oxford University Press
external identifiers
  • pmid:37721482
  • scopus:85186118985
ISSN
0006-8950
DOI
10.1093/brain/awad317
language
English
LU publication?
yes
id
f45d877d-f2f2-4584-8cdd-67e3a77de257
date added to LUP
2024-03-20 11:32:26
date last changed
2024-04-17 11:01:17
@article{f45d877d-f2f2-4584-8cdd-67e3a77de257,
  abstract     = {{<p>Cerebrovascular pathology often co-exists with Alzheimer’s disease pathology and can contribute to Alzheimer’s disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer’s disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (<sup>18</sup>F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ε4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ε4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P &lt; 0.001) and longitudinal tau accumulation (β = 0.11, P &lt; 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = −0.08, P &lt; 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P &lt; 0.001) and between infarcts and plaque density (β = −0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology—in the presence of amyloid-β pathology—modifies tau accumulation in early stages of Alzheimer’s disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer’s disease.</p>}},
  author       = {{Coomans, Emma M. and van Westen, Danielle and Binette, Alexa Pichet and Strandberg, Olof and Spotorno, Nicola and Serrano, Geidy E. and Beach, Thomas G. and Palmqvist, Sebastian and Stomrud, Erik and Ossenkoppele, Rik and Hansson, Oskar}},
  issn         = {{0006-8950}},
  keywords     = {{Alzheimer’s disease; amyloid-β; tau; vascular burden; vascular risk}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{949--960}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Interactions between vascular burden and amyloid-β pathology on trajectories of tau accumulation}},
  url          = {{http://dx.doi.org/10.1093/brain/awad317}},
  doi          = {{10.1093/brain/awad317}},
  volume       = {{147}},
  year         = {{2024}},
}