Abstract

Brain metabolism perturbations can significantly impact traits and diseases. Our study aimed at uncovering metabolic dysfunctions associated with Alzheimer’s disease (AD) and some other human traits. We conducted a genome-wide association study to measure metabolite levels in cerebrospinal fluid (CSF) and brain samples, leading to the identification of 205 independent associations (47.3% of which were novel, spanning 11 previously unreported loci) linked to 139 CSF metabolites, and 32 independent associations (43.8% novel, including 4 new loci) related to 31 brain metabolites. A significant portion of these novel associations (96.9% from CSF and 71.4% from brain) were previously studied in blood or urine. We further examined the identified metabolite quantitative trait loci (MQTLs) in relation to 23 neurological, psychiatric, and common human traits and diseases through colocalization. This integrative approach identified 71 metabolite-trait associations, including the linkage of glycerophosphocholines with Alzheimer's disease, O-sulfo-L-tyrosine with Parkinson’s disease, glycine and xanthine with waist-hip ratio, and ergothioneine with inflammatory bowel disease. These findings significantly enhance our understanding of metabolites' role in the central nervous system and their link to human traits. Additionally, our study explored the systemic metabolic alterations in AD by analyzing brain, CSF, and plasma samples. We identified widespread metabolic disruptions across various pathways, including branched-chain amino acids (BCAA) and methionine-glutathione metabolisms in all sampled tissues. Specific alterations in the brain involved upregulated urea cycles, membrane phospholipid anomalies, and microglia-induced glutamate excitotoxicity. In CSF, altered amino sugar levels possibly indicated blood-brain barrier glycocalyx disruptions. Plasma samples revealed dysregulated urea cycles, increased glutamine levels, and enhanced gut metabolism of aromatic amino acids indicative of hyperammonemia. Elevated ω-oxidation and glycine, carnitine conjugation of plasma fatty acids signified mitochondrial metabolic impairment. Our data further suggested commonalities between AD and type 2 diabetes, evident through elevated phospholipid levels and dysregulated fatty acid metabolism, while differences were noted in the trends of anti-inflammatory kynurenine metabolites and underlying mechanisms of BCAA level increases. Our comprehensive analysis contributes valuable insights into the interconnected or disconnected cerebral and non-cerebral metabolic dysfunctions in AD.

Committee Chair

Carlos Cruchaga

Committee Members

Gabriel Haller; Nancy Saccone; Nathan Stitziel; Sheng Chih Jin

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-24-2026

Language

English (en)

Author's ORCID

https://orcid.org/0000-0001-5253-0490

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Available for download on Saturday, April 22, 2028

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Genetics Commons

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