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Amyloid PET predicts atrophy in older adults without dementia : Results from the AMYPAD Prognostic & Natural History study

Pieperhoff, Leonard ; Lorenzini, Luigi ; Mastenbroek, Sophie LU ; Tranfa, Mario ; Shekari, Mahnaz ; Wink, Alle Meije ; Wolz, Robin ; Grootoonk, Sylke ; Ritchie, Craig and Boada, Mercè , et al. (2025) In NeuroImage: Clinical 48.
Abstract

The impact of amyloid-β (Aβ) accumulation on regional brain atrophy in preclinical Alzheimer’s disease (AD), and its interaction with risk factors like sex and APOE -ε4 carriership, remains unclear. In this study, we examined these associations in a population of older adults without dementia and evaluated the potential of Aβ-PET for risk stratification. We included 1329 participants (56 % female) with an age of 68.2 ± 8.78 years from the prospective multi-center AMYPAD Prognostic and Natural History Study who underwent [18F]Flutemetamol or [18F]Florbetaben Aβ-PET and T1-weighted MRI, with longitudinal data for 684 participants (median follow-up = 3.4 years). Linear mixed models assessed the effect of baseline Aβ... (More)

The impact of amyloid-β (Aβ) accumulation on regional brain atrophy in preclinical Alzheimer’s disease (AD), and its interaction with risk factors like sex and APOE -ε4 carriership, remains unclear. In this study, we examined these associations in a population of older adults without dementia and evaluated the potential of Aβ-PET for risk stratification. We included 1329 participants (56 % female) with an age of 68.2 ± 8.78 years from the prospective multi-center AMYPAD Prognostic and Natural History Study who underwent [18F]Flutemetamol or [18F]Florbetaben Aβ-PET and T1-weighted MRI, with longitudinal data for 684 participants (median follow-up = 3.4 years). Linear mixed models assessed the effect of baseline Aβ burden through the Centiloid approach on longitudinal changes in regional gray matter volume and thickness. Sensitivity analyses were performed in cognitively normal only (CDR = 0) individuals and while correcting for CSF p-tau181 and t-tau. A second model investigated the effects of sex or APOE- ε4 carriership. Baseline global Aβ was predictive of widespread atrophy in several brain regions, most strongly in the fusiform (βVolume = -0.006, βThickness = -0.009), hippocampus (βVolume = -0.005), posterior cingulate (βVolume = -0.006), and precuneus (βVolume = -0.004, βThickness = -0.007), also when investigating only in cognitively normal individuals. Only fusiform atrophy (βp-tau = -0.011; βt-tau = -0.011) remained predicted by Aβ when correcting for p-tau181 or t-tau. Temporal atrophy was exacerbated in women, while frontal, lateral-temporal and hippocampal atrophy was exacerbated by carriership of at least one APOE- ε4 allele, with volumetric loss more sensitive to sex effects and thinning more sensitive to APOE- ε4 effects. Our findings suggest that in older adults with mostly preserved cognition, baseline Aβ-PET predicts future brain atrophy, with fusiform atrophy showing independence from tau pathology and Aβ-dependent atrophy being exacerbated in region-dependent manners in females and APOE -ε4 carriers. Regional cortical volume and thickness may serve as sensitive markers for early Aβ-related neurodegeneration and aid in stratifying risk in AD prevention trials.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Centiloid, Cognitively Unimpaired, Gray Matter Thickness, Gray Matter Volume, MRI, Preclinical Alzheimer’s Disease
in
NeuroImage: Clinical
volume
48
article number
103912
publisher
Elsevier
external identifiers
  • pmid:41270680
  • scopus:105022819101
ISSN
2213-1582
DOI
10.1016/j.nicl.2025.103912
language
English
LU publication?
yes
id
6f21af75-ac5f-4a29-892c-e87a874013cf
date added to LUP
2026-02-09 11:52:48
date last changed
2026-02-09 11:53:57
@article{6f21af75-ac5f-4a29-892c-e87a874013cf,
  abstract     = {{<p>The impact of amyloid-β (Aβ) accumulation on regional brain atrophy in preclinical Alzheimer’s disease (AD), and its interaction with risk factors like sex and APOE -ε4 carriership, remains unclear. In this study, we examined these associations in a population of older adults without dementia and evaluated the potential of Aβ-PET for risk stratification. We included 1329 participants (56 % female) with an age of 68.2 ± 8.78 years from the prospective multi-center AMYPAD Prognostic and Natural History Study who underwent [<sup>18</sup>F]Flutemetamol or [<sup>18</sup>F]Florbetaben Aβ-PET and T1-weighted MRI, with longitudinal data for 684 participants (median follow-up = 3.4 years). Linear mixed models assessed the effect of baseline Aβ burden through the Centiloid approach on longitudinal changes in regional gray matter volume and thickness. Sensitivity analyses were performed in cognitively normal only (CDR = 0) individuals and while correcting for CSF p-tau181 and t-tau. A second model investigated the effects of sex or APOE- ε4 carriership. Baseline global Aβ was predictive of widespread atrophy in several brain regions, most strongly in the fusiform (β<sub>Volume</sub> = -0.006, β<sub>Thickness</sub> = -0.009), hippocampus (β<sub>Volume</sub> = -0.005), posterior cingulate (β<sub>Volume</sub> = -0.006), and precuneus (β<sub>Volume</sub> = -0.004, β<sub>Thickness</sub> = -0.007), also when investigating only in cognitively normal individuals. Only fusiform atrophy (β<sub>p-tau</sub> = -0.011; β<sub>t-tau</sub> = -0.011) remained predicted by Aβ when correcting for p-tau181 or t-tau. Temporal atrophy was exacerbated in women, while frontal, lateral-temporal and hippocampal atrophy was exacerbated by carriership of at least one APOE- ε4 allele, with volumetric loss more sensitive to sex effects and thinning more sensitive to APOE- ε4 effects. Our findings suggest that in older adults with mostly preserved cognition, baseline Aβ-PET predicts future brain atrophy, with fusiform atrophy showing independence from tau pathology and Aβ-dependent atrophy being exacerbated in region-dependent manners in females and APOE -ε4 carriers. Regional cortical volume and thickness may serve as sensitive markers for early Aβ-related neurodegeneration and aid in stratifying risk in AD prevention trials.</p>}},
  author       = {{Pieperhoff, Leonard and Lorenzini, Luigi and Mastenbroek, Sophie and Tranfa, Mario and Shekari, Mahnaz and Wink, Alle Meije and Wolz, Robin and Grootoonk, Sylke and Ritchie, Craig and Boada, Mercè and Marquié, Marta and van der Flier, Wiesje and Vandenberghe, Rik and Hanseeuw, Bernard J. and Martínez-Lage, Pablo and Payoux, Pierre and Visser, Pieter Jelle and Schöll, Michael and Frisoni, Giovanni B. and Stephens, Andrew and Buckley, Christopher and Farrar, Gill and Jessen, Frank and Grau-Rivera, Oriol and Gispert, Juan Domingo and García, David Vállez and Mutsaerts, Henk and Barkhof, Frederik and Collij, Lyduine E.}},
  issn         = {{2213-1582}},
  keywords     = {{Centiloid; Cognitively Unimpaired; Gray Matter Thickness; Gray Matter Volume; MRI; Preclinical Alzheimer’s Disease}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{NeuroImage: Clinical}},
  title        = {{Amyloid PET predicts atrophy in older adults without dementia : Results from the AMYPAD Prognostic & Natural History study}},
  url          = {{http://dx.doi.org/10.1016/j.nicl.2025.103912}},
  doi          = {{10.1016/j.nicl.2025.103912}},
  volume       = {{48}},
  year         = {{2025}},
}