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NEUROIMAGING-DEFINED AMYLOID AND CEREBROVASCULAR PATHOLOGY ARE ASSOCIATED WITH A NEUROMETABOLIC SIGNATURE OF ALZHEIMER’S DISEASE

      Background

      To investigate whether white matter hyperintensities (WMH), an MRI-correlate of small-vessel cerebrovascular disease, are associated with a neurometabolic signature of Alzheimer's disease (AD), defined as the metabolic correlates of preclinical ß-amyloid (Aß) pathology and the apolipoprotein-E ε4 allele (APOE-ε4), the major genetic risk factor for sporadic AD.

      Methods

      Cognitively normal participants (n=30, age=70±5.6 years, MMSE=29.2±1) received 11C-PiB-PET to quantify Aß, 7 Tesla fluid-attenuated inversion recovery MRI to quantitate WMH, and 7 Tesla high-resolution MR spectroscopic imaging to estimate N-acetylaspartate (NAA), myo-inositol (mI), total-choline (tCho), and creatine (Cr) in posterior cingulate and precuneus (PCP) gray and white matter. We examined relationships of Aß, WMH, and APOE-ε4, and their interactions, with brain metabolites.

      Results

      Higher levels of Aß (r= -0.64, p<0.001) and higher WMH volume (r= -0.45, p=0.02) were associated with lower NAA/mI in gray matter. Participants with both high Aß and high WMH had lower NAA/mI compared to those with none or with high level of either Aß or WMH (significant Aß x WMH interaction; F=5.38, p=0.03). APOE-ε4 carriers had lower NAA/mI compared to non-carriers (t=2.24, p=0.03). tCho/Cr in white matter was associated with Aß (r= -0.53 p=0.004) and WMH (r= -0.51; p=0.006); APOE-ε4 carriers with high WMH showed strongest reductions of tCho/Cr (significant APOE-ε4 x WMH interaction, F=6.45, p=0.02).

      Conclusions

      These findings suggest that a neurometabolic signature of AD, defined by metabolic correlates of Aß and APOE-ε4 in older adults, consists of reduced NAA/mI in gray matter and reduced tCho/Cr in white matter. We speculate that these metabolic differences reflect neuronal impairment, glial activation, and altered choline metabolism. This neurometabolic signature of AD is also associated with WMH, both independently and synergistically with Aß and APOE-ε4, emphasizing the importance of small-vessel cerebrovascular disease for AD pathogenesis.