Abstract
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.
Original language | English (US) |
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Pages (from-to) | 980-998 |
Number of pages | 19 |
Journal | Alzheimer's and Dementia |
Volume | 19 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2023 |
Keywords
- Alzheimer's disease
- bioenergetic pathways
- brain
- cholesterol metabolism
- metabolic landscape
- metabolism
- multi-omic integration
- neuroinflammation
- neurotransmission
- osmoregulation
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health