Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

Abstract

Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity.

Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [(18)F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE.

Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [(18)F] flutemetamol tracer ([Formula: see text] = 0.44, p = 0.02 and [Formula: see text] = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = -0.16, p = 0.02), independently of amyloid pathology.

Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology.

Figure 1. Voxel placement, example spectra, and metabolite levels across diagnostic groups

(A) Single voxel prescribed midsagittally on a T1-weighed image. Examples of spectra obtained from the 2 × 2 × 2 cm³ voxel collected at echo time 30 ms in (B) a cognitively healthy control and (C) a patient with mild cognitive impairment (MCI). Metabolite levels across different stages of predementia Alzheimer disease (D–F). (D) Myo-inositol (mI)/creatine (Cr) ratio levels across diagnostic subgroups. (E) N-acetylaspartate (NAA)/Cr ratio levels across diagnostic subgroups. (F) Choline (Cho)/Cr ratio levels across diagnostic subgroups. Tukey honestly significant difference tests were used for post hoc comparisons. Significance levels: *p < 0.05, **p < 0.01, ***p < 0.001. CTL Aβ42− = controls with CSF Aβ42 >530 ng/L; CTL Aβ42+ = controls with CSF Aβ42 ≤530 ng/L; SCD Aβ42+ = patients with subjective cognitive decline with CSF Aβ42 ≤530 ng/L; MCI Aβ42+ = patients with MCI with CSF Aβ42 ≤530 ng/L.

Figure 2. Associations between myo-inositol (mI)/creatine (Cr) and Aβ plaque load and functional connectivity

(A) Association between mI/Cr in posterior cingulate cortex (PCC)/precuneus and Aβ plaque load measured by [¹⁸F]-flutemetamol PET in CSF Aβ42-positive controls: a significant association between mI/Cr and plaque load ( = 0.42, t = 2.62, p = 0.02). (B) Association between mI/Cr in PCC/precuneus and functional connectivity. The sum of each participant's seed-voxel correlation within a normal connectivity mask correlated significantly with mI/Cr levels in the seed region across participants from all groups, r_pearson = −0.16 (p = 0.02). The inset shows the seed position in precuneus (in blue) and the thresholded average normal connectivity of CSF Aβ42-negative controls used to define the normal connectivity mask. CTL Aβ42− = controls with CSF Aβ42 >530 ng/L; CTL Aβ42+ = controls with CSF Aβ42 ≤530 ng/L; SCD Aβ42+ = patients with subjective cognitive decline with CSF Aβ42 ≤530 ng/L; MCI Aβ42+ = patients with mild cognitive impairment with CSF Aβ42 ≤530 ng/L.

Figure 3. Concentrations of myo-inositol (mI)/creatine (Cr) in posterior cingulate cortex/precuneus in the diagnostic subgroups stratified by APOE ε4 carriership

Levels of mI/Cr differed significantly between carriers and noncarriers in the subgroup of CSF Aβ42-negative controls (t = −3.61, p < 0.001). CTL Aβ42− = controls with CSF Aβ42 >530 ng/L; CTL Aβ42+ = controls with CSF Aβ42 ≤530 ng/L; SCD Aβ42+ = patients with subjective cognitive decline with CSF Aβ42 ≤530 ng/L; MCI Aβ42+ = patients with mild cognitive impairment with CSF Aβ42 ≤530 ng/L.