Astrocytic function is associated with both amyloid-β and tau pathology in non-demented APOE ε4 carriers

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 he an important link between the APOE epsilon 4 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 epsilon 4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE epsilon 4, myo-inositol and Alzheimer's disease pathology (arnyloid-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 epsilon 4 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-beta and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioHNDER-2 cohort. APOE genotype impacted the associations between myo-inositol and amyloid-beta 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 epsilon 4 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 epsilon 4 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 epsilon 4 carriers: P < 0.01; APOE epsilon 4 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 epsilon 4. Therefore, we suggest that myo-inositol is a candidate in vivo marker to study the impact of APOE epsilon 4 on the interplay between astrocytes and the pathophysiology of Alzheimer's disease.

Automated summary

This study provides further evidence of the important role of astrocytes in the pathophysiology of Alzheimer's disease and investigates the relationship between APOE genotype, myo-inositol concentration, and Alzheimer's disease pathology. The results show an interaction between myo-inositol concentration and amyloid-beta deposition in APOE ε4 carriers.