You may have heard Alzheimer’s described as type 3 diabetes, due to a shift in the way the brain uses glucose for energy. This description is often accompanied by the admonition that we should consume less sugar and that our modern, sugar-laden diet is causing Alzheimer’s.
A new study explains some of what is going on in the brain as far as Alzheimer’s, APOE type, and using sugar for brain energy. 1
The study, published in the journal Dementia, shows that carrying the APOE4 allele may cause a shift in brain cells away from efficient mitochondrial energy production toward more reliance on glycolysis, alongside increased oxidative stress and inflammatory signaling.
These changes are seen in young APOE4 mice and in human cell lines of astrocytes and neurons, which points to brain metabolism being disrupted long before amyloid-β or tau pathology develops.
A little background for context:
The APOE E4 allele is one of the strongest genetic risk factors for late-onset Alzheimer’s disease. APOE4 brains and astrocytes have reduced APOE expression, mitochondrial dysfunction, more oxidative stress -- and a stronger reliance on glycolysis for ATP production.
The brain uses a lot of ATP for moving ions and driving the ion gradients for neuronal signaling. While glucose metabolism is responsible for 95% of the ATP production in the brain, in healthy brain cells, most of the ATP is produced in the mitochondria via the TCA cycle and oxidative phosphorylation, with glycolysis (in the cytosol) supplying a little ATP. Neurons can also use ketones when glucose is not available. Astrocytes tend to rely more on glycolysis to meet the quick energy demands, and they have relatively fewer mitochondria. They then supply lactate to nearby neurons, which is then used in the TCA cycle for ATP production.2
Back to the study:
In this new study, the APOE4 neurons also show altered mitochondrial function and upregulated inflammatory and immune response pathways (including interferon and the HLA system). This points to a link between disturbed energy metabolism and neuroimmune activation in APOE4, which has also been seen in a bunch of prior studies.
Additionally, the APOE4 neurons showed downregulation of cholesterol biosynthesis, vitamin A metabolism, and protein phosphorylation (we will come back to this one). APOE is a cholesterol carrier, and the E4 allele has long been known to alter cholesterol in the brain. Importantly, these bioenergetic changes occur in the absence of amyloid and tau, pointing to the idea that APOE4-driven metabolic and inflammatory stress may be an upstream driver of Alzheimer’s risk. Essentially, this suggests that brain metabolism is disrupted long before amyloid or tau pathology develops.
Immune system activation:
Comments
Nothing yet. Say the first thing.
Sign in to join the conversation.