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Astrocytic function is associated with both amyloid-β and tau pathology in non-demented APOE 4 carriers

Spotorno, Nicola LU ; Najac, Chlocrossed D.Sign© ; Stomrud, Erik LU orcid ; Mattsson-Carlgren, Niklas LU orcid ; Palmqvist, Sebastian LU orcid ; Van Westen, Danielle LU orcid ; Ronen, Itamar and Hansson, Oskar LU orcid (2022) In Brain Communications 4(3).
Abstract

A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer's disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ϵ4 allele and the development of Alzheimer's disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there is conflicting evidence regarding the relationship between APOE ϵ4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE ϵ4, myo-inositol and Alzheimer's disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer's... (More)

A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer's disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ϵ4 allele and the development of Alzheimer's disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there is conflicting evidence regarding the relationship between APOE ϵ4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE ϵ4, myo-inositol and Alzheimer's disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer's disease are limited. A previous study revealed differences in myo-inositol levels between APOE ϵ4 carriers and non-carriers already in preclinical Alzheimer's disease participants. However, other reports showed no impact of APOE genotype on the association between myo-inositol and the rate of amyloid-beta accumulation. In the present study, we determined the effect of APOE genotype on the association between myo-inositol and both amyloid-β and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. APOE genotype impacted the associations between myo-inositol and amyloid-β pathology as revealed by an interaction effect between APOE genotype and levels of myo-inositol (P < 0.001) such that higher myo-inositol concentration was related to more amyloid-beta pathology in APOE ϵ4 carriers only. A similar interaction effect was also found when investigating the effect of APOE on the association between myo-inositol and tau pathology (P < 0.01). Focusing on the APOE ϵ4 subsample, myo-inositol partially (17%) mediated the association between amyloid-beta and tau pathology (P < 0.05). Furthermore, in a subgroup of participants with available plasma levels of glial fibrillary acidic protein, a marker of astroglial activation and astrocytosis, we found that glial fibrillary acidic protein correlated with myo-inositol only in APOE e4 carriers (APOE ϵ4 carriers: P < 0.01; APOE ϵ4 non-carriers: P > 0.8), suggesting that myo-inositol might reflect an aspect of the astrocytic involvement in Alzheimer's pathology which is specific to the impact of APOE ϵ4. Therefore, we suggest that myo-inositol is a candidate in vivo marker to study the impact of APOE ϵ4 on the interplay between astrocytes and the pathophysiology of Alzheimer's disease.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, amyloid-β, APOE, astrocytes, myo-inositol
in
Brain Communications
volume
4
issue
3
article number
fcac135
publisher
Oxford University Press
external identifiers
  • pmid:35702728
  • scopus:85136142950
ISSN
2632-1297
DOI
10.1093/braincomms/fcac135
language
English
LU publication?
yes
id
1998d517-bf03-432c-8e34-cfc6ca02f2e8
date added to LUP
2022-10-14 11:27:49
date last changed
2024-04-18 14:58:41
@article{1998d517-bf03-432c-8e34-cfc6ca02f2e8,
  abstract     = {{<p>A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer's disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ϵ4 allele and the development of Alzheimer's disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there is conflicting evidence regarding the relationship between APOE ϵ4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE ϵ4, myo-inositol and Alzheimer's disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer's disease are limited. A previous study revealed differences in myo-inositol levels between APOE ϵ4 carriers and non-carriers already in preclinical Alzheimer's disease participants. However, other reports showed no impact of APOE genotype on the association between myo-inositol and the rate of amyloid-beta accumulation. In the present study, we determined the effect of APOE genotype on the association between myo-inositol and both amyloid-β and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. APOE genotype impacted the associations between myo-inositol and amyloid-β pathology as revealed by an interaction effect between APOE genotype and levels of myo-inositol (P &lt; 0.001) such that higher myo-inositol concentration was related to more amyloid-beta pathology in APOE ϵ4 carriers only. A similar interaction effect was also found when investigating the effect of APOE on the association between myo-inositol and tau pathology (P &lt; 0.01). Focusing on the APOE ϵ4 subsample, myo-inositol partially (17%) mediated the association between amyloid-beta and tau pathology (P &lt; 0.05). Furthermore, in a subgroup of participants with available plasma levels of glial fibrillary acidic protein, a marker of astroglial activation and astrocytosis, we found that glial fibrillary acidic protein correlated with myo-inositol only in APOE e4 carriers (APOE ϵ4 carriers: P &lt; 0.01; APOE ϵ4 non-carriers: P &gt; 0.8), suggesting that myo-inositol might reflect an aspect of the astrocytic involvement in Alzheimer's pathology which is specific to the impact of APOE ϵ4. Therefore, we suggest that myo-inositol is a candidate in vivo marker to study the impact of APOE ϵ4 on the interplay between astrocytes and the pathophysiology of Alzheimer's disease.</p>}},
  author       = {{Spotorno, Nicola and Najac, Chlocrossed D.Sign© and Stomrud, Erik and Mattsson-Carlgren, Niklas and Palmqvist, Sebastian and Van Westen, Danielle and Ronen, Itamar and Hansson, Oskar}},
  issn         = {{2632-1297}},
  keywords     = {{Alzheimer's disease; amyloid-β; APOE; astrocytes; myo-inositol}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain Communications}},
  title        = {{Astrocytic function is associated with both amyloid-β and tau pathology in non-demented APOE 4 carriers}},
  url          = {{http://dx.doi.org/10.1093/braincomms/fcac135}},
  doi          = {{10.1093/braincomms/fcac135}},
  volume       = {{4}},
  year         = {{2022}},
}