It has been known since the 1960’s that the brain prefers glucose on a normal mixed diet and switches over to ketones only on a ketogenic diet, or after several days of fasting.
The reason for the switch during starvation is not because ketones are a super fuel for the brain, but to reduce the body’s need for gluconeogenesis. This in turn has a “protein sparing” effect on muscle.
This is made clear from the charts below, summarizing classic studies of starvation. Volunteers who were eating a normal mixed diet, meaning one in which most of the calories came from carbohydrates, starved for 40 days. During that time, researchers measured fuels going in and out of different tissues and organs.
Note that even after 36 hours of fasting, glucose is the sole fuel for the brain. Where does glucose come from during this period, after liver glycogen stores are exhausted? Gluconeogenesis. Follow the arrow backward from the brain and you seen that muscle protein provides most of the carbons for this pathway. The fasted man is losing 75 g of muscle protein per day to satisfy the need for glucose homeostasis.
During this period, adipose tissue is releasing fatty acids into the blood. The liver takes part of this pool and synthesizes 60 g ketone bodies for other tissues to use. But the brain is not using them yet. During this period, the brain is up-regulating the genes for ketone body transporters.
Skip down to the second chart, which shows a man adapted to starvation. Now the brain is using both ketones and glucose as fuels, but importantly, much less glucose than during the beginning of the fast. Trace back to the muscle and you see our man is losing only 20 g of protein per day as compared to 75 g. This is the protein sparing effect of ketosis.
Ketone bodies are a preferred fuel on a ketogenic diet because they are present in such high amounts.
Note that the brain always needs glucose. Even if ketones supply most of the ATP, glucose is needed for biosynthetic reactions and other cell functions.
Charts adapted from Fig 30–7, Lehninger, 2nd Edition.