Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy

Abstract

Background: Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed.

Methods: We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies.

Results: Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B.

Discussion: Our findings underscore vast alterations in the brain's metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP.

Highlights: First high-throughput metabolic comparison of Alzheimer's diesease (AD) versus progressive supranuclear palsy (PSP) in brain tissue. Cerebellar cortex (CER) shows substantial AD-related metabolic changes, despite limited proteinopathy. AD impacts both CER and temporal cortex (TCX); PSP's changes are primarily in CER. AD and PSP share metabolic alterations despite major pathological differences.

Keywords: Alzheimer's disease; brain; cognitive deficit; metabolism; mitochondrial dysfunction; neuroinflammation; oxidative stress; progressive supranuclear palsy; tau‐mediated stress.

FIGURE 1

Study overview: 342 Mayo Clinic Brain Bank samples were included in this analysis. For each sample, diagnosis and demographic information were available. Metabolomic profiling was performed on samples from the cerebellar cortex (CER) and temporal cortex (TCX) regions. Metabolic signatures of each diagnosis, namely, Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) in comparison to metabolic profiles of controls without neurodegenerative disease. A comparison of the metabolic signatures of the two tauopathies was performed, highlighting the overlap in altered metabolites and metabolic pathways commonly dysregulated in the two diseases.

FIGURE 2

Overview of metabolites and their associations with Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). (A) Distribution of metabolites detected by metabolomics platform across metabolic classes. (B) Number of metabolic associations for each brain region and each disease. (C) Overlap of metabolic associations between the two diseases in cerebellar cortex samples. (D) Overlap of metabolic associations between the two diseases in temporal cortex samples.

FIGURE 3

Functional annotation of metabolic signatures in the cerebellar cortex (CER) region. Within the CER region, for each disease and pathway, the number of positively or negatively associated metabolites is shown in orange and green boxes, respectively. These pathways are further annotated by super‐pathways. The significance of these pathways in one or both diseases is shown per pathway. Venn diagram depicts the overlap of the number of significant pathways in the two diseases. FA, fatty acid; LC, long chain.

FIGURE 4

Comparison of deregulated pathways in the two diseases. Within the cerebellar cortex region, 35 pathways were exclusively dysregulated in Alzheimer's disease (AD), 18 pathways were shared between the two diseases, and 1 pathway was dysregulated exclusively in progressive supranuclear palsy (PSP). The labeled processes indicate selected pathways discussed in the text. Included for illustrative purposes are stylistic representations of the tau isoform associated with each tauopathy. Within these protein structures, residues in R1–R4 and in the C‐terminal domain are colored purple, blue, green, gold, and orange, respectively.