Brain and blood metabolome for Alzheimer's dementia: findings from a targeted metabolomics analysis.

The development of Alzheimer's dementia (AD) accompanies both central and peripheral metabolic disturbance, but the metabolic basis underlying AD and metabolic markers predictive of AD risk remain to be determined. It is also unclear whether the metabolic changes in the peripheral blood and brain are overlapping in relation to AD. The present study addresses these questions by targeted metabolomics in both antemortem blood and postmortem brain samples in 2 community-based longitudinal cohorts of aging and dementia. We found that higher serum levels of 3 acylcarnitines, including decanoylcarnitine (C10), pimelylcarnitine (C7-DC), and tetradecadienylcarnitine (C14:2), significantly predict a lower risk of incident AD (composite hazard ratio = 0.368, 95% CI [0.207, 0.653]) after an average of 4.5-year follow-up, independent of age, sex, and education. In addition, baseline serum levels of ten glycerophospholipids, one amino acid, and 5 acylcarnitines predict the longitudinal change in cognitive functions. Moreover, 28 brain metabolites were associated with AD phenotypes. Of the putative metabolites identified in the serum and brain, 4 metabolites (3 glycerophospholipids [PC aa C30:0, PC ae C34:0, PC ae C36:1] and 1 acylcarnitine [C14:2]) were present in both the postmortem brain and antemortem blood, but only one metabolite (C14:2) was associated with AD in the same direction (i.e., protective). Partial correlation and network analyses suggest a potential tissue-specific regulation of metabolism, although other alternatives exist. Together, we identified significant associations of both central and peripheral metabolites with AD phenotypes, but there seems to be little overlap between the 2 tissues.