Targeted Metabolomic Analysis in Alzheimer’s Disease Plasma and Brain Tissue in Non-Hispanic Whites

Abstract

Background: Metabolites are biological compounds reflecting the functional activity of organs and tissues. Understanding metabolic changes in Alzheimer’s disease (AD) can provide insight into potential risk factors in this multifactorial disease and suggest new intervention strategies or improve non-invasive diagnosis. Objective: In this study, we searched for changes in AD metabolism in plasma and frontal brain cortex tissue samples and evaluated the performance of plasma measurements as biomarkers. Methods: This is a case-control study with two tissue cohorts: 158 plasma samples (94 AD, 64 controls; Texas Alzheimer’s Research and Care Consortium – TARCC) and 71 postmortem cortex samples (35 AD, 36 controls; Banner Sun Health Research Institute brain bank). We performed targeted mass spectrometry analysis of 630 compounds (106 small molecules: UHPLC-MS/MS, 524 lipids: FIA-MS/MS) and 232 calculated metabolic indicators with a metabolomic kit (Biocrates MxP® Quant 500). Results: We discovered disturbances (FDR≤0.05) in multiple metabolic pathways in AD in both cohorts including microbiome-related metabolites with pro-toxic changes, methylhistidine metabolism, polyamines, corticosteroids, omega-3 fatty acids, acylcarnitines, ceramides, and diglycerides. In AD, plasma reveals elevated triglycerides, and cortex shows altered amino acid metabolism. A cross-validated diagnostic prediction model from plasma achieves AUC = 82% (CI95 = 75–88%); for females specifically, AUC = 88% (CI95 = 80–95%). A reduced model using 20 features achieves AUC = 79% (CI95 = 71–85%); for females AUC = 84% (CI95 = 74–92%). Conclusion: Our findings support the involvement of gut environment in AD and encourage targeting multiple metabolic areas in the design of intervention strategies, including microbiome composition, hormonal balance, nutrients, and muscle homeostasis.

Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue

“…Previous studies have linked HHcy to changes in neuroimaging measures such as brain atrophy, white matter hyperintensities, and infarcts or cognitive performance, 30 , 31 while only a small number of studies have examined associations of HHcy with dementia‐related neuropathologies. 27 , 32 , 33 While there are a significant number of animal studies suggesting mechanisms for HHcy‐induced damage, there has been no robust human autopsy studies to evaluate these potential mechanisms. The present pilot study evaluated associations of HHcy with pathologic features in 31 autopsied research volunteers who had an ante mortem range of plasma tHcy from 4.8 to 27.3 µmol/L.…”

“…Hyperhomocysteinemia is a risk factor for stroke, VCID, and AD; however, studies linking HHcy to neuropathologic hallmarks of dementia remain lacking. Previous studies have linked HHcy to changes in neuroimaging measures such as brain atrophy, white matter hyperintensities, and infarcts or cognitive performance, 30,31 while only a small number of studies have examined associations of HHcy with dementia‐related neuropathologies 27,32,33 . While there are a significant number of animal studies suggesting mechanisms for HHcy‐induced damage, there has been no robust human autopsy studies to evaluate these potential mechanisms.…”

Metabolic and Transcriptomic Signatures of the Acute Psychological Stress Response in the Mouse Brain

“…Furthermore, 5-aminovaleric acid, which is endogenously synthesized or derived from the metabolism of lysine by gut microbiota, is also known to act as a methylene homolog of gamma-aminobutyric acid (GABA) and functions as a weak GABA agonist [ 80 ]. Recently, 5-aminovaleric acid was identified in the plasma and brain tissues of Alzheimer’s disease patients [ 81 ]. It is currently unclear whether 5-aminovaleric acid could play a role in the stress response, presumably through synaptic modulation.…”

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

“…However, more studies are needed to highlight its significance as an indication of TCA impairment [ 87 , 100 ]. Additionally, Kalecký et al also observed elevated levels of aconitic and succinic acids [ 101 ]. Another example of such a compound is acylcarnitines, whose plasma levels in AD patients are significantly higher than in controls.…”