The landscape of metabolic brain alterations in Alzheimer's disease

Alzheimers Dement. 2022 Jul 13:10.1002/alz.12714. doi: 10.1002/alz.12714. Online ahead of print.


Introduction: Alzheimer's 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 the brain has been missing.

Methods: We 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.

Results: We 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 amyloid beta pathology.

Discussion: This work provides a comprehensive reference map of metabolic brain changes in AD that lays the foundation for future mechanistic follow-up studies.

Keywords: Alzheimer's disease; bioenergetic pathways; brain; cholesterol metabolism; metabolic landscape; metabolism; multi-omic integration; neuroinflammation; neurotransmission; osmoregulation.

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