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APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles.

ABSTRACT: Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [¹⁸F]AZD4694), tau ([¹⁸F]MK6240), and microglial activation ([¹¹C]PBR28). We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

SUBMITTER: Ferrari-Souza JP

PROVIDER: S-EPMC10075966 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles.

Ferrari-Souza João Pedro JP Lussier Firoza Z FZ Leffa Douglas T DT Therriault Joseph J Tissot Cécile C Bellaver Bruna B Ferreira Pâmela C L PCL Malpetti Maura M Wang Yi-Ting YT Povala Guilherme G Benedet Andréa L AL Ashton Nicholas J NJ Chamoun Mira M Servaes Stijn S Bezgin Gleb G Kang Min Su MS Stevenson Jenna J Rahmouni Nesrine N Pallen Vanessa V Poltronetti Nina Margherita NM O'Brien John T JT Rowe James B JB Cohen Ann D AD Lopez Oscar L OL Tudorascu Dana L DL Karikari Thomas K TK Klunk William E WE Villemagne Victor L VL Soucy Jean-Paul JP Gauthier Serge S Souza Diogo O DO Zetterberg Henrik H Blennow Kaj K Zimmer Eduardo R ER Rosa-Neto Pedro P Pascoal Tharick A TA

Science advances 20230405 14

Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOE< ...[more]

PMID: 37018391

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Project description:BackgroundAlthough APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy).MethodsCombining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR).ResultsCompared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059).ConclusionsBy triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

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APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles.

Publications

<i>APOE</i>ε4 associates with microglial activation independently of Aβ plaques and tau tangles.

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