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

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. 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.

• Authors: Gemma Salvadó, Michel J Grothe, Colin Groot, Alexis Moscoso, Michael Schöll, Juan Domingo Gispert, Rik Ossenkoppele, Alzheimer’s Disease Neuroimaging Initiative
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 48 Issue 7 Pg. 2212-2224 (07 2021) ISSN: 1619-7089 [Electronic] Germany
• PMID: 33521872 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Apolipoprotein E2
• Apolipoprotein E4
• tau Proteins

Topics

• Aged
• Alleles
• Alzheimer Disease (diagnostic imaging, genetics)
• Amyloid beta-Peptides (genetics)
• Apolipoprotein E2 (genetics)
• Apolipoprotein E4 (genetics)
• Cross-Sectional Studies
• Genotype
• Humans
• Positron-Emission Tomography
• tau Proteins (genetics)