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Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia

Salvadó, Gemma ; Grothe, Michel J. ; Groot, Colin ; Moscoso, Alexis ; Schöll, Michael LU ; Gispert, Juan Domingo and Ossenkoppele, Rik LU (2021) In European Journal of Nuclear Medicine and Molecular Imaging 48(7). p.2212-2224
Abstract

Purpose: To examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer’s disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia. Methods: We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models.... (More)

Purpose: To examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer’s disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia. Methods: We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau. Results: Compared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]: − 0.31 [− 0.45, − 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (βstd range: 0.27-0.51, all p < 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10 [− 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ. Conclusion: Our data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amyloid-β, APOE, Cognition, Cross-sectional, Hippocampal volumes, Longitudinal, PET, Sex interaction, Tau
in
European Journal of Nuclear Medicine and Molecular Imaging
volume
48
issue
7
pages
13 pages
publisher
Springer
external identifiers
  • scopus:85100014160
  • pmid:33521872
ISSN
1619-7070
DOI
10.1007/s00259-021-05192-8
language
English
LU publication?
yes
id
850af862-e059-4ca3-aa14-6138d503e48f
date added to LUP
2021-02-10 09:02:30
date last changed
2024-06-13 07:00:24
@article{850af862-e059-4ca3-aa14-6138d503e48f,
  abstract     = {{<p>Purpose: To examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer’s disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia. Methods: We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([<sup>18</sup>F]florbetapir or [<sup>18</sup>F]florbetaben) and tau ([<sup>18</sup>F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau. Results: Compared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (β<sub>std</sub> [95% confidence interval (CI)]: − 0.31 [− 0.45, − 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (β<sub>std</sub> [95%CI]: 0.64 [0.42, 0.82], p &lt; 0.001) and tau burden (β<sub>std</sub> range: 0.27-0.51, all p &lt; 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (β<sub>std</sub> [95%CI]: 0.10 [− 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ. Conclusion: Our data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.</p>}},
  author       = {{Salvadó, Gemma and Grothe, Michel J. and Groot, Colin and Moscoso, Alexis and Schöll, Michael and Gispert, Juan Domingo and Ossenkoppele, Rik}},
  issn         = {{1619-7070}},
  keywords     = {{Amyloid-β; APOE; Cognition; Cross-sectional; Hippocampal volumes; Longitudinal; PET; Sex interaction; Tau}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  pages        = {{2212--2224}},
  publisher    = {{Springer}},
  series       = {{European Journal of Nuclear Medicine and Molecular Imaging}},
  title        = {{Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia}},
  url          = {{http://dx.doi.org/10.1007/s00259-021-05192-8}},
  doi          = {{10.1007/s00259-021-05192-8}},
  volume       = {{48}},
  year         = {{2021}},
}