Alzheimer's disease (AD) is characterized by a loss of metabolic flexibility that leads to bioenergetic failure.
AD may be better understood as a disorder of rather than just a disease of metabolic dysfunction.
In the healthy brain, cells dynamically switch between fuel sources to meet energy demands, a capability that deteriorates in AD.
Microglia in AD shift towards glycolytic metabolism and prioritize immune responses, which can deplete the brain's energy supply.
The metabolic changes in AD occur in two phases: an initial hypermetabolic state driven by inflammation, followed by a later hypometabolic phase that causes energy collapse and neuronal dysfunction.
Alterations in metabolism are associated with increased amyloid-β production and tau release, which may further exacerbate disease progression.
Evidence from various studies indicates that shifts in metabolism correlate with cognitive decline and the presence of amyloid and tau pathology.
Simplified
Alzheimer's disease (AD) is more than just amyloid and tau. While often described as a disease of metabolic dysfunction, AD can more accurately be described as a disorder of that leads to bioenergetic failure. In the healthy brain, neurons, glia, and vascular cells dynamically share and switch between different fuel sources (e.g., glucose, lactate, ketones, and fatty acids) to match functional demand. In AD, this adaptability is progressively lost because cellular metabolism is actively reprogrammed to support neuroinflammatory and disease-associated processes at the cost of neuronal function. Microglia, in particular, upregulate glycolytic metabolism, alter lipid handling, and prioritize immune functions, which actively depletes the brain's energy supply. These adaptations are initially compensatory but ultimately trap the brain in a rigid metabolic program that deprioritizes neuronal support. This metabolic shift unfolds along a biphasic trajectory: early, glia-driven hypermetabolism aligned with inflammation, followed by late-stage brain hypometabolism and energy collapse that leads to neuronal dysfunction. System-level consequences include altered excitability, decreased network connectivity, sleep disruption, and cognitive decline. Critically, these changes feed forward to accelerate AD pathogenesis: glycolytically biased microglia and stressed neurons promote amyloid-β production, tau release, and protein aggregation, adding to metabolic rigidity. Evidence from human neuroimaging studies, brain/cerebral spinal fluid (CSF) multi-omic studies, and preclinical studies demonstrate that shifts in glycolytic flux, tricarboxylic acid cycle (TCA) intermediates, and lipid metabolism parallel amyloid and tau pathology and cognition decline. We hypothesize that these metabolic programs, while initially protective, are chronically maladaptive yet reversible. We propose that restoring metabolic flexibility can mitigate amyloid and tau pathology, neuronal loss, and functional decline. Ongoing preclinical studies and clinical trials are actively exploring metabolism as a therapeutic target in AD. Collectively, these findings define AD as a disorder of metabolic inflexibility, where adaptive shifts in cellular metabolism become pathologically rigid and drive disease progression, while offering a promising target for therapeutic intervention in AD.
Full Text
We can’t show the full text here under this license.
