Early myo-inositol changes may precede Aβ pathology and relate to APOE genotype in Alzheimer disease

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

Methods:
In this cross-sectional multi-center study (a subset of the prospective Swedish BioFINDER study) we included four groups, representing the different stages of pre-dementia AD: i) cognitively healthy elderly with normal cerebrospinal fluid (CSF) amyloid-β42, ii) cognitively healthy elderly with pathologic CSF amyloid-β42, iii) patients with subjective cognitive decline and pathologic CSF amyloid-β42, iv) patients with mild cognitive decline and pathologic CSF amyloid-β42 (N total=352). Spectroscopic markers measured in the posterior cingulate/precuneus, were considered alongside known disease biomarkers: CSF amyloid-β42, phosphorylated-tau, total-tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk-factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in myo- inositol/creatine and myo-inositol/n-acetyl-aspartate levels compared to amyloid-negative healthy elderly (p<0.05). In amyloid-positive healthy elderly, myo-inositol/creatine and myo-inositol/n-acetyl-aspartate correlated with cortical retention of [18F]-flutemetamol tracer (β=0.44, p=0.02 and β=0.51, p=0.01 respectively). Further, healthy elderly APOE ε4 carriers with normal CSF amyloid-β42 levels had significantly higher myo-inositol/creatine levels (p<0.001) than ε4 non-carriers. Finally, elevated myo-inositol/creatine was associated with decreased functional connectivity within the default mode network (rpearson=-0.16, p=0.02), independently of amyloid-β pathology. Conclusions: Myo-inositol levels are elevated already at asymptomatic stages of AD. Moreover, myo-inositol/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ levels, suggesting that myo-inositol levels may reveal regional brain consequences of APOE ε4 before detectable amyloid-β pathology.

Results:
Amyloid-positive cognitively healthy participants showed a significant increase in myo- inositol/creatine and myo-inositol/n-acetyl-aspartate levels compared to amyloid-negative healthy elderly (p<0.05). In amyloid-positive healthy elderly, myo-inositol/creatine and myo-inositol/n-acetyl-aspartate correlated with cortical retention of [18F]-flutemetamol tracer (β=0.44, p=0.02 and β=0.51, p=0.01 respectively). Further, healthy elderly APOE ε4 carriers with normal CSF amyloid-β42 levels had significantly higher myo-inositol/creatine levels (p<0.001) than ε4 non-carriers. Finally, elevated myo-inositol/creatine was associated with decreased functional connectivity within the default mode network (rpearson=-0.16, p=0.02), independently of amyloid-β pathology. Conclusions: Myo-inositol levels are elevated already at asymptomatic stages of AD. Moreover, myo-inositol/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ levels, suggesting that myo-inositol levels may reveal regional brain consequences of APOE ε4 before detectable amyloid-β pathology.

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