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BackgroundMyo‐inositol (MI) is a presumed marker for glial activation which can be quantified by non‐invasive Magnetic Resonance Spectroscopy (MRS) and is suspected to be elevated in early Alzheimer’s disease (AD). In the framework of the NeuroMET2 project, we investigated the relationship between MI and other AD‐relevant measures.MethodsAbsolute concentrations of MI were measured by 7 tesla MRS in the posterior cingulate cortex (PCC)/precuneus of 26 cognitively healthy individuals (HC), 23 patients with subjective cognitive decline (SCD), 23 with mild cognitive impairment (MCI) and 24 with dementia due to suspected AD. Using linear models, MI’s association with memory ability (NeuroMET Memory Metric), volumes of the hippocampus and PCC/precuneus, and seed‐based functional connectivity were investigated. Interaction terms involving the apolipoprotein E (APOE) ε4 allele were analyzed additionally. All models were adjusted to age and education and weighted based on Cramér‐Lao lower bounds.ResultsAbsolute MI concentrations were substantially elevated in AD patients (adjusted mean [95% CI]=8.5 mmol/l [7.8; 9.3]). However, there were no relevant differences between SCD (6.7 mmol/l [6.0; 7.3]) or MCI (7.5 mmol/l [6.8; 8.2]) and participants of the HC group (7.2 mmol/l [6.6, 7.9]). Across the whole cohort, higher levels of MI were associated with lower memory ability (ß [95% CI]=‐0.31 [‐0.44; ‐0.17], std. ß=‐0.40, p<0.001), smaller hippocampus volume (ß=‐59.89 [‐131.40; 11.62], std. ß=‐0.16, p=0.100) and lower seed‐based functional connectivity (ß=‐3948.41 [‐6480.69; ‐1416.13], std. ß=‐0.34, p=0.003). There was no relevant effect between MI and PCC/precuneus volume (ß=83.27 [‐117.89; 284.43], std. ß=0.08, p=0.413). Finally, there was no substantial mediation effect of APOE ε4 carriership on the association between MI and neither memory ability (ß=0.09 [‐0.18; 0.36], std. ß=0.37, p=0.519), hippocampus volume (ß=‐55.60 [‐223.48; 112.29], std. ß=‐0.45, p=0.511), PCC/precuneus volume (ß=‐110.68 [‐546.22; 324.86], std. ß=‐0.32, p=0.614) nor seed‐based functional connectivity (ß=2009.46 [‐4207.40; 8226.32], std. ß=0.55, p=0.520).ConclusionsAcross a cohort with participants ranging from healthy to AD, we showed that glial activation, measured by MI concentration, was associated with key AD‐related processes. The potential of MI as a non‐invasive biomarker for increasing memory impairment in pre‐dementia stages remains to be explored in longitudinal studies.