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Peer-reviewedCC BYAlzheimer's & dementia : the journal of the Alzheimer's Association

APOE ε4 gene dose drives a canonical and predictable topography of amyloid deposition.

  • Augusto J Mendes1,2
  • Cecilia Boccalini3
  • Federica Ribaldi1,2
  • Michela Pievani4
  • Débora Peretti3
  • Valentina Garibotto3,5,6
  • Andrea Chincarini7
  • Giovanni B Frisoni1,2
  • Alzheimer's Disease Neuroimaging Initiative
7 affiliations
  1. 1Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.
  2. 2Geneva Memory Center, Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland.
  3. 3Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocenter and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  4. 4Laboratory of Alzheimer's Neuroimaging and Epidemiology (LANE), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
  5. 5Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland.
  6. 6CIBM Center for Biomedical Imaging, Geneva, Switzerland.
  7. 7Genoa section, National Institute of Nuclear Physics (INFN), Rome, Genoa, Italy.
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Abstract

Introduction

Apolipoprotein E ε4 (APOE ε4) carriership is associated with higher amyloid burden in Alzheimer's disease (AD), but whether it constrains the spatial predictability of amyloid deposition at the individual level remains unknown.Methods

We analyzed voxel-wise amyloid positron emission tomography data from 781 amyloid-positive individuals across two independent cohorts (Alzheimer's Disease Neuroimaging Initiative and Geneva Memory Center), spanning the full clinical continuum. Individual topographic similarity to canonical AD amyloid maps and within-group spatial homogeneity were assessed via voxel-wise correlations and linear regression adjusted for age, sex, and global amyloid burden.Results

APOE ε4 carriers exhibited amyloid distributions more aligned with canonical AD topographies than non-carriers (p < 0.001), with a clear gene-dose effect on within-group spatial homogeneity: Homozygotes showed the highest inter-subject consistency, followed by heterozygotes and non-carriers. Effects were robust across tracers, clinical stages, and cohorts.Discussion

APOE ε4 gene dose constrains the spatial predictability of amyloid accumulation, informing genotype-stratified approaches in anti-amyloid trials.

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Cite

BibTeXRIS
BibTeX
@article{mendes2026apoe,
  title = {{APOE ε4 gene dose drives a canonical and predictable topography of amyloid deposition.}},
  author = {Augusto J Mendes and Cecilia Boccalini and Federica Ribaldi and Michela Pievani and Débora Peretti and Valentina Garibotto and Andrea Chincarini and Giovanni B Frisoni and Alzheimer's Disease Neuroimaging Initiative},
  journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
  year = {2026},
  month = oct,
  doi = {10.1002/alz.71935},
  url = {https://europepmc.org/article/MED/42957970},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - APOE ε4 gene dose drives a canonical and predictable topography of amyloid deposition.
AU  - Augusto J Mendes
AU  - Cecilia Boccalini
AU  - Federica Ribaldi
AU  - Michela Pievani
AU  - Débora Peretti
AU  - Valentina Garibotto
AU  - Andrea Chincarini
AU  - Giovanni B Frisoni
AU  - Alzheimer's Disease Neuroimaging Initiative
PY  - 2026
DA  - 2026/10/01
JO  - Alzheimer's & dementia : the journal of the Alzheimer's Association
DO  - 10.1002/alz.71935
UR  - https://europepmc.org/article/MED/42957970
AB  - Introduction  Apolipoprotein E ε4 (APOE ε4) carriership is associated with higher amyloid burden in Alzheimer's disease (AD), but whether it constrains the spatial predictability of amyloid deposition at the individual level remains unknown.Methods  We analyzed voxel-wise amyloid positron emission tomography data from 781 amyloid-positive individuals across two independent cohorts (Alzheimer's Disease Neuroimaging Initiative and Geneva Memory Center), spanning the full clinical continuum. Individual topographic similarity to canonical AD amyloid maps and within-group spatial homogeneity were assessed via voxel-wise correlations and linear regression adjusted for age, sex, and global amyloid burden.Results  APOE ε4 carriers exhibited amyloid distributions more aligned with canonical AD topographies than non-carriers (p < 0.001), with a clear gene-dose effect on within-group spatial homogeneity: Homozygotes showed the highest inter-subject consistency, followed by heterozygotes and non-carriers. Effects were robust across tracers, clinical stages, and cohorts.Discussion  APOE ε4 gene dose constrains the spatial predictability of amyloid accumulation, informing genotype-stratified approaches in anti-amyloid trials.
SN  - 1552-5260
SN  - 1552-5279
ER  -