Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-beta

Cicognola, Claudia LU orcid ; Salvadó, Gemma LU ; Smith, Ruben LU ; Palmqvist, Sebastian LU orcid ; Stomrud, Erik LU orcid ; Betthauser, Tobey ; Johnson, Sterling ; Janelidze, Shorena LU ; Mattsson-Carlgren, Niklas LU orcid and Hansson, Oskar LU orcid , et al. (2025) In Brain : a journal of neurology
Abstract

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). While APOE4 is strongly associated with amyloid-beta (Aβ), its relationship with tau accumulation is less understood. Studies evaluating the role of APOE4 on tau accumulation showed conflicting results, particularly regarding the independence of these associations from Aβ load. In this study, we examined three independent longitudinal cohorts (BioFINDER-1, BioFINDER-2 and WRAP) in which participants had cross-sectional and longitudinal measures of tau tangles (tau-PET; temporal meta-ROI and entorhinal) or soluble p-tau (p-tau217), Aβ-PET and APOE genotype. The study included a total of 1370 cognitively unimpaired (CU) and 449 mild cognitive... (More)

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). While APOE4 is strongly associated with amyloid-beta (Aβ), its relationship with tau accumulation is less understood. Studies evaluating the role of APOE4 on tau accumulation showed conflicting results, particularly regarding the independence of these associations from Aβ load. In this study, we examined three independent longitudinal cohorts (BioFINDER-1, BioFINDER-2 and WRAP) in which participants had cross-sectional and longitudinal measures of tau tangles (tau-PET; temporal meta-ROI and entorhinal) or soluble p-tau (p-tau217), Aβ-PET and APOE genotype. The study included a total of 1370 cognitively unimpaired (CU) and 449 mild cognitive impairment (MCI) subjects, followed longitudinally with tau-PET and p-tau217. APOE4 carriers accounted for 40.2-50% of the cohorts. Different linear regressions (cross-sectional) and linear mixed-effect models (longitudinal) with tau measures as outcomes were fitted to test the effect of APOE4 as independent predictor, as well as in combination with baseline Aβ load (including interaction). All models included age, sex and cognitive status as covariates. We found no independent effects of the APOE4 carriership on insoluble tau in either cohort (BioFINDER-2 or WRAP), both on cross-sectional and longitudinal tau-PET in the temporal meta-ROI, when Aβ was present in the model (p=0.531-0.949). Aβ alone was the best predictor of insoluble tau accumulation, with no interaction between APOE4 and Aβ on tau-PET. In BioFINDER-2, there was a significant interaction between APOE4 and Aβ (b=0.166, p<0.001) in the entorhinal cortex at baseline. However, the interaction was not present in WRAP PET. No independent effects of the APOE4 carriership on baseline (p=0.683-0.708) and longitudinal (p=0.188-0.570) soluble p-tau217 were observed when Aβ was included in the model in BioFINDER-1 and WRAP. Similarly, no interaction between APOE4 and Aβ on soluble p-tau217 was observed. Mediation analysis revealed that Aβ load fully mediated most associations between APOE4 and tau (46-112%, either cross-sectional or longitudinal tau-PET or soluble p-tau217). In the largest cohort (BioFINDER-2), looking at APOE4 groups by number of ε4 alleles, we found an interaction between APOE4 homozygotes and Aβ on tau-PET levels at baseline and over time in the temporal meta-ROI, while in the entorhinal cortex this effect was observed only at baseline. In conclusion, although APOE4 is strongly associated with Aβ aggregation, it seems to be minimally associated with longitudinal changes in soluble or insoluble p-tau levels at a given level of Aβ pathology, confirming the primacy of Aβ in driving tau pathology.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Brain : a journal of neurology
publisher
Oxford University Press
external identifiers
  • pmid:39817469
ISSN
1460-2156
DOI
10.1093/brain/awaf016
language
English
LU publication?
yes
additional info
© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.
id
82e64b6c-5440-4b9f-94bb-bf2585e6963f
date added to LUP
2025-01-23 10:25:39
date last changed
2025-04-04 14:27:42
@article{82e64b6c-5440-4b9f-94bb-bf2585e6963f,
  abstract     = {{<p>The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). While APOE4 is strongly associated with amyloid-beta (Aβ), its relationship with tau accumulation is less understood. Studies evaluating the role of APOE4 on tau accumulation showed conflicting results, particularly regarding the independence of these associations from Aβ load. In this study, we examined three independent longitudinal cohorts (BioFINDER-1, BioFINDER-2 and WRAP) in which participants had cross-sectional and longitudinal measures of tau tangles (tau-PET; temporal meta-ROI and entorhinal) or soluble p-tau (p-tau217), Aβ-PET and APOE genotype. The study included a total of 1370 cognitively unimpaired (CU) and 449 mild cognitive impairment (MCI) subjects, followed longitudinally with tau-PET and p-tau217. APOE4 carriers accounted for 40.2-50% of the cohorts. Different linear regressions (cross-sectional) and linear mixed-effect models (longitudinal) with tau measures as outcomes were fitted to test the effect of APOE4 as independent predictor, as well as in combination with baseline Aβ load (including interaction). All models included age, sex and cognitive status as covariates. We found no independent effects of the APOE4 carriership on insoluble tau in either cohort (BioFINDER-2 or WRAP), both on cross-sectional and longitudinal tau-PET in the temporal meta-ROI, when Aβ was present in the model (p=0.531-0.949). Aβ alone was the best predictor of insoluble tau accumulation, with no interaction between APOE4 and Aβ on tau-PET. In BioFINDER-2, there was a significant interaction between APOE4 and Aβ (b=0.166, p&lt;0.001) in the entorhinal cortex at baseline. However, the interaction was not present in WRAP PET. No independent effects of the APOE4 carriership on baseline (p=0.683-0.708) and longitudinal (p=0.188-0.570) soluble p-tau217 were observed when Aβ was included in the model in BioFINDER-1 and WRAP. Similarly, no interaction between APOE4 and Aβ on soluble p-tau217 was observed. Mediation analysis revealed that Aβ load fully mediated most associations between APOE4 and tau (46-112%, either cross-sectional or longitudinal tau-PET or soluble p-tau217). In the largest cohort (BioFINDER-2), looking at APOE4 groups by number of ε4 alleles, we found an interaction between APOE4 homozygotes and Aβ on tau-PET levels at baseline and over time in the temporal meta-ROI, while in the entorhinal cortex this effect was observed only at baseline. In conclusion, although APOE4 is strongly associated with Aβ aggregation, it seems to be minimally associated with longitudinal changes in soluble or insoluble p-tau levels at a given level of Aβ pathology, confirming the primacy of Aβ in driving tau pathology.</p>}},
  author       = {{Cicognola, Claudia and Salvadó, Gemma and Smith, Ruben and Palmqvist, Sebastian and Stomrud, Erik and Betthauser, Tobey and Johnson, Sterling and Janelidze, Shorena and Mattsson-Carlgren, Niklas and Hansson, Oskar and Pichet Binette, Alexa}},
  issn         = {{1460-2156}},
  language     = {{eng}},
  month        = {{01}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-beta}},
  url          = {{http://dx.doi.org/10.1093/brain/awaf016}},
  doi          = {{10.1093/brain/awaf016}},
  year         = {{2025}},
}