Hemispheric Asymmetry of Tau Pathology is Related to Asymmetric Amyloid Deposition in Alzheimer’s Disease

Abstract The distribution of tau pathology in Alzheimer’s disease (AD) shows remarkable inter-individual heterogeneity, including hemispheric asymmetry. However, the factors driving this asymmetry remain poorly understood. We explored whether tau asymmetry is linked to i) reduced inter-hemispheric brain connectivity (potentially restricting tau spread), or ii) asymmetry in amyloid-beta (Aβ) distribution (indicating greater hemisphere-specific vulnerability to AD pathology). 452 participants from the Swedish BioFINDER-2 cohort with evidence of both Aβ pathology (CSF Aβ42/40 or neocortical Aβ-PET) and tau pathology (temporal tau-PET), were categorised as left asymmetric (n=102), symmetric (n=306), or right asymmetric (n=44) based on temporal lobe tau-PET uptake distribution. Edge-wise inter-hemispheric functional (RSfMRI; n=318) and structural connectivity (dMRI; n=352) patterns were examined but no differences in inter-hemispheric functional or structural connectivity were found between groups. However, a strong association was observed between tau and Aβ laterality patterns based on PET uptake (n=233; β=0.632, p<0.001), which was replicated in three independent cohorts (n=234; β=0.535, p<0.001). In a longitudinal Aβ-positive sample, baseline Aβ asymmetry predicted the progression of tau laterality over time (n=289; β=0.025, p=0.028). These findings suggest that tau asymmetry is not associated with a weaker inter-hemispheric connectivity but might reflect hemispheric differences in vulnerability to Aβ pathology, underscoring the role of regional vulnerability in determining the distribution of AD pathology. Competing Interest Statement O.H. is an employee of Eli Lilly and Lund University. R.S. has received consultancy/speaker fees from Eli Lilly, Novo Nordisk, Roche and Triolab. S.P. has acquired research support (for the institution) from ki elements / ADDF and Avid. In the past 2 years, he has received consultancy/speaker fees from Bioartic, Esai, Eli Lilly, Novo Nordisk, and Roche. N.M.C. has received consultancy/speaker fees from Biogen, Eli Lilly, Owkin, and Merck. The precursor of [18F]flutemetamol was sponsored by GE Healthcare. The other authors declare no competing interests. Footnotes ↵** One of the datasets used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf ↵# shared senior authorship