Ketones, omega-3 fatty acids and the Yin-Yang balance in the brain: insights from infant development and Alzheimer's disease, and implications for human brain evolution

Optimal brain performance is intimately linked to the brain's Yin and the Yang - the balance between its structure and its energy metabolism. This relationship is clearly exemplified in infant brain development and in Alzheimer's disease, and probably also applies to human brain evolution. In these examples, redundant pathways help achieve this important balance. For instance, the key structural lipid for the brain, docosahexaenoic acid (DHA), is supplied to the infant brain from at last three overlapping sources: (i) milk; (ii) infant's own fat stores and (iii) by some endogenous synthesis from alpha-linolenic acid (ALA) or eicosapentaenoic acid (EPA). On the energy side, glucose is normally the brain's main fuel but under conditions of prolonged starvation, it can be almost totally replaced by the ketone bodies, acetoacetate and beta-hydroxybutyrate. When ketones are present in the blood they spare glucose uptake by the brain because they are actually the brain's preferred fuel and are essential for normal infant brain development. The redundant sources of ketones are long chain fatty acids (including the relatively ketogenic ALA) in infant stores, and medium chain triglycerides (MCT) in milk. Besides infancy, nowhere is the strain on the brain's balance between yin and yang more apparent than in Alzheimer's disease (AD). One of the reasons why attempts to treat AD have largely failed could well be because chronically inadequate glucose supply to some areas of the brain on the order of 10% is present in people at risk of AD long before cognitive decline begins. However, brain ketone uptake is still normal even in moderately advanced AD. Hence, treatments that ignore the brain energy (glucose) deficit in AD would be predicted to fail, but treatments that attempt to rescue brain fuel availability via ketones would be predicted to have a better chance of succeeding. By analogy to ketones sparing glucose for brain energy metabolism, perhaps ALA or EPA entering the brain can help spare (conserve) DHA for its structural role. If so, it would not necessarily be futile to transport ALA and EPA into the brain just to beta-oxidize the majority afterwards; DHA sparing as well as ketone production could be important beneficiaries.