HAI Book 2025 - Flipbook - Page 213
Diez, Ibai
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Unveiling the heterogeneity of tau spreading in aging and Alzheimer's
disease using polygenic combinations: Towards personalized models
Ibai Diez1,2,3,4, Cristina Lois1, Jorge Garcia Condado3,5, Michelle E Farrell5, Emma G Thibault1,
Heidi I.L. Jacobs2, Rachel F. Buckley5,6, Bernard J Hanseeuw1,7, Michael J. Properzi5, Hyun-Sik
Yang5,8, Reisa Sperling2,5,8, Jesus M. Cortes3,4,9, Yakeel T. Quiroz5,10,11, Jorge Sepulcre12, Keith
Johnson1,2,5,8, Teresa Gomez-Isla5,13
1
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA, Boston, MA, US
2
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital,
Harvard Medical School, Charlestown, MA, USA, Charlestown, MA, US
3
Computational Neuroimaging Lab, Biobizkaia Health Research Institute, Barakaldo, Spain, Barakaldo, ES
4
IKERBASQUE Basque Foundation for Science, Bilbao, Spain, Bilbao, ES
5
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA,
Boston, MA, US
6
Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia, Melbourne, AU
7
Department of Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium,
Bruxelles, BE
8
Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Boston,
MA, USA, Boston, MA, US
9
Department of Cell Biology and Histology, University of the Basque Country, Leioa, Bizkaia, Spain, Leioa, ES
10
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA,
Boston, MA, US
11
The Neuroscience Group of Antioquia, University of Antioquia, Medell1́n, Colombia, Medllin, CO
12
Yale PET Center, Yale Medical School, Yale University, New Haven, CT, USA, New Haven, CT, US
13
Mass General Institute for Neurodegenerative Disease, Charlestown, MA, USA., Charlestown, MA, US
Tau pathology spreading in the brain was traditionally thought to be consistent across individuals with Alzheimer9s
disease (AD). However, recent neuroimaging, clinical and neuropathologic studies suggest high inter-individual
variability in tau spreading patterns. This variability could explain the observed differences in clinical
presentation, age of onset, disease progression, and affected cognitive domains (like memory, language, or
visuospatial or executive function). We hypothesize that distinct polygenic combinations of 98 genetic risk loci for
late-onset AD can provide a more precise characterization of the observed heterogeneity.
In this study, we analyzed genetic information and Flortaucipir PET data from 792 individuals from ADNI (n=478)
and A4/ELearn (n=314) studies (619 cognitively normal, 153 mild cognitive impairment (MCI), and 20 AD; age 74.0 ±
6.8; 55% female) to investigate the association between different polygenic combinations and tau spreading
patterns in aging and AD. As PET outcome, we used partial volume corrected (three-compartment Muller-Gartner
MG Method) SUVr (reference: inferior cerebellar grey matter). Using tau spreading models, we identified a tau
spreading backbone network and observed four distinct tau spreading subnetworks consistent with previously
reported AD subtypes: limbic, medial temporal lobe sparing, lateral temporal, and posterior (Fig 1). Additionally, we
identified genetic variants linked to specific subtypes of tau pathology and unique patterns of tau spreading (Fig
2). Moreover, combinations of these genetic factors revealed mixed subtypes.
This study offers new observations that connect individual genetics to the diverse manifestations of tau
pathology in AD, providing a more comprehensive explanation for the variations in tau spread severity and spatial
distribution among individuals. While incorporating individual genetic makeup could enhance current AD
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