Figure 2. Trajectory of mitochondrial function, substrate utilization during AD progression and therapeutic strategy.

At young age or in healthy aging, brain metabolic activity is supported by glucose, the primary fuel source, whereas in prodromal and incipient AD the antecedent decline in glucose metabolism is first paralleled by compensatory activation of ketogenic pathways, which later diminishes and progresses into local fatty acid oxidation and white matter degeneration. The prevention strategy aims to enhance the glucose driven mitochondrial bioenergetics to promote healthy aging and prevent AD. Alternatively, in prodromal and incipient AD, sustained activation of ketogenesis provides prolonged supplement of the alternative fuel source, ketone bodies, and therefore sustains mitochondrial bioenergetic function and prevents/delays further progression of the disease. At the middle to late stage of AD, rather than modifying disease progression, treatments merely offer symptom relief.