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

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.