The landscape of metabolic brain alterations in Alzheimer's disease

Batra, R.; Arnold, M.; Woerheide, M.; Allen, M.; Wang, X.; Blach, C.; Levey, A. I.; Seyfried, N.; Ertekin-Taner, N.; Bennett, D. A.; Kastenmüller, G.; Kaddurah-Daouk, R.; Krumsiek, J.

doi:10.1101/2021.11.15.468698

bioRxiv · 10.1101/2021.11.15.468698

The landscape of metabolic brain alterations in Alzheimer's disease

Batra, R.·Arnold, M.·Woerheide, M.·Allen, M.·Wang, X.·Blach, C.·Levey, A. I.·Seyfried, N.·Ertekin-Taner, N.·Bennett, D. A.·Kastenmüller, G.·Kaddurah-Daouk, R.·Krumsiek, J.

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Abstract

INTRODUCTIONAlzheimers disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in brain has been missing. METHODSWe metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures. RESULTSWe observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than {beta}-amyloid pathology. DISCUSSIONThis work provides a comprehensive reference map of metabolic brain changes in AD which lays the foundation for future mechanistic follow-up studies.

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Batra, R., Arnold, M., Woerheide, M., Allen, M., Wang, X., Blach, C., Levey, A. I., Seyfried, N., Ertekin-Taner, N., Bennett, D. A., Kastenmüller, G., Kaddurah-Daouk, R., Krumsiek, J.. 2021-11-19. The landscape of metabolic brain alterations in Alzheimer's disease. https://doi.org/10.1101/2021.11.15.468698

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