Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease

Abstract

Down syndrome (DS) is a well‐known neurodevelopmental disorder most commonly caused by trisomy of chromosome 21. Because individuals with DS almost universally develop heavy amyloid burden and Alzheimer's disease (AD), biomarker discovery in this population may be extremely fruitful. Moreover, any AD biomarker in DS that does not directly involve amyloid pathology may be of high value for understanding broader mechanisms of AD generalizable to the neurotypical population. In this retrospective biomarker discovery study, we examined banked peripheral plasma samples from 78 individuals with DS who met clinical criteria for AD at the time of the blood draw (DS‐AD) and 68 individuals with DS who did not (DS‐NAD). We measured the relative abundance of approximately 5,000 putative features in the plasma using untargeted mass spectrometry (MS). We found significantly higher levels of a peak putatively annotated as lactic acid in the DS‐AD group (q = .014), a finding confirmed using targeted MS (q = .011). Because lactate is the terminal product of glycolysis and subsequent lactic acid fermentation, we performed additional targeted MS focusing on central carbon metabolism which revealed significantly increased levels of pyruvic (q = .03) and methyladipic (q = .03) acids in addition to significantly lower levels of uridine (q = .007) in the DS‐AD group. These data suggest that AD in DS is accompanied by a shift from aerobic respiration toward the less efficient fermentative metabolism and that bioenergetically derived metabolites observable in peripheral blood may be useful for detecting this shift.

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

“…The same process (impaired mitochondrial function, and the resulting compensatory upregulation of glycolysis) would also produce increases in systemic lactate production (again, a common observation in septic shock, where, in fact, elevated lactate levels are excellent predictors of mortality); indeed, our meta-analysis has clearly demonstrated that DS cells produce increased levels of lactate (Fig. 4 c) and clinical studies have also reported elevated plasma lactate levels in DS individuals (Caracausi et al 2018 ; Gross et al 2019 ).…”

Brain pyrimidine nucleotide synthesis and Alzheimer disease

“…If lower UCK2 mRNA levels in different brain regions correspond with a decrease in pyrimidine synthesis pathway, and, as it has been recently reported, AD subjects show lower uridine concentrations in plasma and cerebrospinal fluid [55–59], then AD patients probably have a cerebral deficiency in many cellular functions related to the metabolism of uridine. Therefore, it can be suggested that uridine therapeutic administration would improve biochemical pathways related to brain function.…”

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

“…Formimidoyltransferase cyclodeaminase (FTCD) is another gene located on the long arm of HSA21, which encodes an enzyme that participates in histidine and folate metabolism, both essential for purine, pyrimidines, and amino acids biosynthesis. In addition, aberrant metabolism of adenosine, homocysteine, and folate was also observed in DS (Patterson, 2009;Gross et al, 2019).…”

“…With regard to brain alterations, accumulation of toxic catabolites (Caracausi et al, 2018;Gross et al, 2019) or dysfunction of key metabolic pathways were identified as crucial determinants triggering neuronal dyshomeostasis and neurodegeneration in DS (Head et al, 2018;Lott and Head, 2019;Vacca et al, 2019).…”