In Alzheimer’s disease (AD), there are early significant deficits in glucose utilization that become increasingly severe as disease progresses.
Most reports from early-onset AD animal models find that these energy deficits are largely due to defects in , and possibly to mitochondrial fusion and fission regulators. Animal models of tauopathy demonstrate Complex I deficits.
In AD-vulnerable brain regions with early glucose utilization deficits, surviving neurons show large reductions in mitochondrial complex I, IV, and V gene expression and proteins. These changes appear sufficient to to cognitive deficits. These are not by nondemented individuals, even in the presences of AD pathology.
The precise causes of reduced glucose utilization in AD are unknown, but may reflect these mitochondrial deficits, as well as defective insulin signaling. These changes lead to adenosine triphosphate deficits and disruptions in the balance of NAD+/NADH, both of which are already altered by normal aging.
However, because metabolism is coupled to synaptic activity, it is difficult to ascertain whether these “bioenergetic” deficits are simply secondary to progressive or a to neuron and synapse loss and cognitive deficits.
One of the best ways to discern the contribution of bioenergetics deficits is to treat them. Many animal models and some small trials appear to show possible from supplements directed at improving energy metabolism.
In the context of these known deficits in Alzheimer’s, the new positive results with ketogenic diet reported by Dr. Swerdlow should not be ignored despite the small sample size and open-label design with the diet. The impressive 4-5 point increase in ADAS-cog that they saw is not easily achieved, and the rapid loss with washout suggests a real benefit with a large effect size.
Similarly, despite the study’s limitations with dose and size, Dr. Cunnane’s imaging of ketone body uptake and its correlation with cognitive improvement suggests that ameliorating energy deficits can be a real target capable of producing substantial short-term benefits for patients with Alzheimer’s.
Given the rapid results and large effect size, this is an area that needs to see more trials.