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Hemispheric Asymmetry of Amyloid Deposition Influences Asymmetric Tau Pathology in Alzheimer’s Disease

Anijärv, Toomas Erik LU orcid ; Smith, Ruben LU ; Collij, Lyduine E. LU ; Behjat, Harry H. LU ; Binette, Alexa Pichet LU ; Rittmo, Jonathan LU orcid ; Karlsson, Linda LU orcid ; Strandberg, Olof LU ; van Westen, Danielle LU orcid and Vogel, Jacob W. LU , et al. (2025) In Alzheimer's & dementia : the journal of the Alzheimer's Association 21(S8).
Abstract

BACKGROUND: Tau pathology distribution in Alzheimer's disease (AD) shows individual spatial heterogeneity, including hemispheric asymmetry. The mechanisms underlying this asymmetry remain unclear. This study explored whether tau asymmetry is linked to reduced inter-hemispheric connectivity, potentially restricting tau spread, or reflects asymmetry in amyloid-beta (Aβ) distribution, indicating hemisphere-specific vulnerability to early Aβ pathology. METHOD: The study included 837 Aβ-positive (CSF Aβ42/40<0.08 or cortical Aβ-PET>1.033) participants from the Swedish BioFINDER-2 cohort with available tau-PET scan(s). A cross-sectional subsample of 452 subjects with evidence of tau pathology based on temporal meta-ROI (Braak I-IV;... (More)

BACKGROUND: Tau pathology distribution in Alzheimer's disease (AD) shows individual spatial heterogeneity, including hemispheric asymmetry. The mechanisms underlying this asymmetry remain unclear. This study explored whether tau asymmetry is linked to reduced inter-hemispheric connectivity, potentially restricting tau spread, or reflects asymmetry in amyloid-beta (Aβ) distribution, indicating hemisphere-specific vulnerability to early Aβ pathology. METHOD: The study included 837 Aβ-positive (CSF Aβ42/40<0.08 or cortical Aβ-PET>1.033) participants from the Swedish BioFINDER-2 cohort with available tau-PET scan(s). A cross-sectional subsample of 452 subjects with evidence of tau pathology based on temporal meta-ROI (Braak I-IV; SUVR>1.362) was selected and categorised as left asymmetric (n = 102), symmetric (n = 306), or right asymmetric (n = 44) using a laterality index (LI; see Figure 1). First, edge-wise inter-hemispheric structural (diffusion-MRI, n = 352) and functional (rs-fMRI, n = 318) connectivity were compared between the tau asymmetry groups using the Desikan-Killiany parcellation. Only the top 10% inter-hemispheric connections identified in a separate control sample were analysed. Second, the association between Aβ and tau laterality patterns was investigated using linear regression on LI values and validated in three independent cohorts (OASIS-3, A4, ADNI). Finally, in a longitudinal subsample (n = 289; average follow-up = 2.9 years) of Aβ-positive participants with multiple tau-PET scans, stratified into A+T- (n = 180) and A+T+ (n = 109) groups based on pathology at baseline, linear mixed effect models were used to assess the association between baseline Aβ laterality and tau laterality change over time. RESULT: Cross-sectionally, no differences in average edge-wise inter-hemispheric functional or structural connectivity were found between tau asymmetric and symmetric groups (Figure 2a). In contrast, a strong association was observed between tau and Aβ laterality patterns (Figure 2b; β=0.632, p <0.001), which was replicated in three independent cohorts (Figure 2c; all p <0.005). In the longitudinal A+ sample, the degree of Aβ asymmetry at baseline predicted progression of tau laterality over time (Figure 3a; β=0.025, p = 0.028), with the strongest interaction effect in the Braak III-IV meta-ROI in A+T- individuals (Figure 3b; β=0.080, p <0.001) but not in A+T+ (Figure 3c). CONCLUSION: These findings suggest that tau asymmetry is not associated with differences in macro-scale inter-hemispheric individual connectivity but reflects hemispheric differences in vulnerability to Aβ pathology.

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type
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publication status
published
subject
in
Alzheimer's & dementia : the journal of the Alzheimer's Association
volume
21
issue
S8
article number
e110048
publisher
Wiley
external identifiers
  • scopus:105025738065
  • pmid:41433515
ISSN
1552-5279
DOI
10.1002/alz70862_110048
language
English
LU publication?
yes
id
f7f3d6ba-9b46-463b-b2ab-45723c310c5a
date added to LUP
2026-02-11 14:31:14
date last changed
2026-02-12 08:31:52
@misc{f7f3d6ba-9b46-463b-b2ab-45723c310c5a,
  abstract     = {{<p>BACKGROUND: Tau pathology distribution in Alzheimer's disease (AD) shows individual spatial heterogeneity, including hemispheric asymmetry. The mechanisms underlying this asymmetry remain unclear. This study explored whether tau asymmetry is linked to reduced inter-hemispheric connectivity, potentially restricting tau spread, or reflects asymmetry in amyloid-beta (Aβ) distribution, indicating hemisphere-specific vulnerability to early Aβ pathology. METHOD: The study included 837 Aβ-positive (CSF Aβ42/40&lt;0.08 or cortical Aβ-PET&gt;1.033) participants from the Swedish BioFINDER-2 cohort with available tau-PET scan(s). A cross-sectional subsample of 452 subjects with evidence of tau pathology based on temporal meta-ROI (Braak I-IV; SUVR&gt;1.362) was selected and categorised as left asymmetric (n = 102), symmetric (n = 306), or right asymmetric (n = 44) using a laterality index (LI; see Figure 1). First, edge-wise inter-hemispheric structural (diffusion-MRI, n = 352) and functional (rs-fMRI, n = 318) connectivity were compared between the tau asymmetry groups using the Desikan-Killiany parcellation. Only the top 10% inter-hemispheric connections identified in a separate control sample were analysed. Second, the association between Aβ and tau laterality patterns was investigated using linear regression on LI values and validated in three independent cohorts (OASIS-3, A4, ADNI). Finally, in a longitudinal subsample (n = 289; average follow-up = 2.9 years) of Aβ-positive participants with multiple tau-PET scans, stratified into A+T- (n = 180) and A+T+ (n = 109) groups based on pathology at baseline, linear mixed effect models were used to assess the association between baseline Aβ laterality and tau laterality change over time. RESULT: Cross-sectionally, no differences in average edge-wise inter-hemispheric functional or structural connectivity were found between tau asymmetric and symmetric groups (Figure 2a). In contrast, a strong association was observed between tau and Aβ laterality patterns (Figure 2b; β=0.632, p &lt;0.001), which was replicated in three independent cohorts (Figure 2c; all p &lt;0.005). In the longitudinal A+ sample, the degree of Aβ asymmetry at baseline predicted progression of tau laterality over time (Figure 3a; β=0.025, p = 0.028), with the strongest interaction effect in the Braak III-IV meta-ROI in A+T- individuals (Figure 3b; β=0.080, p &lt;0.001) but not in A+T+ (Figure 3c). CONCLUSION: These findings suggest that tau asymmetry is not associated with differences in macro-scale inter-hemispheric individual connectivity but reflects hemispheric differences in vulnerability to Aβ pathology.</p>}},
  author       = {{Anijärv, Toomas Erik and Smith, Ruben and Collij, Lyduine E. and Behjat, Harry H. and Binette, Alexa Pichet and Rittmo, Jonathan and Karlsson, Linda and Strandberg, Olof and van Westen, Danielle and Vogel, Jacob W. and Stomrud, Erik and Palmqvist, Sebastian and Mattsson-Carlgren, Niklas and Ossenkoppele, Rik and Spotorno, Nicola and Hansson, Oskar}},
  issn         = {{1552-5279}},
  language     = {{eng}},
  note         = {{Conference Abstract}},
  number       = {{S8}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's & dementia : the journal of the Alzheimer's Association}},
  title        = {{Hemispheric Asymmetry of Amyloid Deposition Influences Asymmetric Tau Pathology in Alzheimer’s Disease}},
  url          = {{http://dx.doi.org/10.1002/alz70862_110048}},
  doi          = {{10.1002/alz70862_110048}},
  volume       = {{21}},
  year         = {{2025}},
}