Metabolic Dysregulation in Alzheimer's Disease and Neurodegeneration

Alzheimer’s disease (AD) and related neurodegenerative disorders are increasingly recognised as conditions in which disturbed energy metabolism plays a central role. A hallmark feature of AD is cerebral glucose hypometabolism, evident from early stages of the disease and often preceding clinical symptoms. Impaired insulin signalling and resistance within the brain exacerbate accumulation of amyloid-β and hyperphosphorylated tau, while mitochondrial dysfunction and oxidative stress further undermine neuronal viability. Altered function and expression of glucose transporters at the blood–brain barrier and within neural cells diminish substrate delivery, compounding energetic deficits. Lipid metabolism disturbances, chronic low-grade inflammation and dysregulated neuroglial metabolic coupling also contribute to synaptic failure and neuronal loss. Collectively, these interlinked pathways define a landscape in which metabolic insufficiency drives proteopathic cascades and neurodegeneration, offering both mechanistic insight and novel therapeutic avenues targeting brain energy homeostasis.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Metabolic Dysregulation in Alzheimer's Disease and Neurodegeneration publication trend

The graph below shows the total number of articles in metabolic dysregulation in alzheimer's disease and neurodegeneration across all publications each year (not limited to Nature Index journals).

Technical terms

Glucose hypometabolism: A state of reduced cerebral glucose uptake and utilisation, often detected by imaging and associated with early neurodegenerative changes.

Insulin resistance: A diminished cellular response to insulin signalling, leading to impaired glucose transport and metabolic derailment in neurons and glia.

NLRP3 inflammasome: A multiprotein complex in innate immune cells that, when activated, triggers inflammatory cytokine release and can influence brain glucose handling.

Astrocyte–Neuron Lactate Shuttle: A metabolic coupling mechanism whereby astrocytes convert glucose to lactate and supply it to neurons as an alternative energy substrate.

KATP channels: ATP-sensitive potassium channels that link cellular energy status to membrane excitability and can modulate amyloid-β release under hyperglycaemic conditions.

References

1. Characterization of preclinical Alzheimer’s disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology. Alzheimer's Research & Therapy (2024).
2. Inhibiting NLRP3 Inflammasome Activation by CY-09 Helps to Restore Cerebral Glucose Metabolism in 3×Tg-AD Mice. Antioxidants (2023).
3. KATP channels are necessary for glucose dependent increases in amyloid-beta and Alzheimer’s-related pathology. JCI Insight (2023).
4. Glucose transporters in brain in health and disease. Pflügers Archiv - European Journal of Physiology (2020).
5. Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits. Frontiers in Neuroscience (2018).
6. The roles of lipid and glucose metabolism in modulation of β-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Frontiers in Aging Neuroscience (2015).
7. Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?. Frontiers in Neuroscience (2020).
8. Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives. Frontiers in Physiology (2022).