Fueling the Alzheimer’s brain with fat

Induced ketogenesis trial

Inducing ketosis through diet seems to help correct the normal, age-related decline in the brain’s ability to use glucose, said Stephen Cunnane, PhD, who also presented ketogenic intervention results at AAIC. “Cognitively normal, healthy older adults experience a 10% reduction in the brain’s ability to metabolize glucose compared to healthy young people,” he said in an interview. But this decline accelerates as Alzheimer’s hits. Those with early AD have a 20% decrement in glucose utilization, compared with healthy elders.

Changes in brain glucose metabolism can develop years before any cognitive symptoms manifest and seem to increase the risk of Alzheimer’s, said Dr. Cunnane of Sherbrooke University, Que.

“We propose that this vicious cycle of presymptomatic glucose hypometabolism causes chronic brain energy deprivation, and might contribute to deteriorating neuronal function. That could cause a further decrease in the demand for glucose, leading to cognitive decline.”

“What doesn’t change, though, is the brain’s ability to take up ketone bodies,” he said. If anything, the brain appears to use ketones more efficiently as AD becomes established. “It’s almost like the brain is trying to rescue itself. If those cells were dead, they would not be able to take up ketones. Because they do, we think they are instead starving because of their inability to use glucose and that maybe we can rescue them with ketones before they die.”

At AAIC, Dr. Cunnane reported interim results of an investigation of induced ketogenesis in patients with mild cognitive impairment (MCI). The 6-month BENEFIC trial comprises 50 patients, randomized to either a daily nutritional supplement with 30 g medium chain triglycerides (MCT) in a unflavored, nondairy emulsion, or a fat-equivalent placebo drink. When consumed, the liver very quickly converts MCT fatty acids into ketone bodies, which then circulate throughout the body, including passing the blood-brain barrier.

All of the participants in the BENEFIC trial underwent brain PET scanning for both glucose and ketone uptake. Early results clearly showed that the MCI brains took up just as much acetoacetate as did the brains of cognitively normal young adults. And although the study wasn’t powered for a full cognitive assessment, Dr. Cunnane did present 6-month data on three measures in the MCI group: trail making time, verbal fluency, and the Boston Naming Test. In the active group on MCT, scores on all three measures improved “modestly” in direct correlation with brain ketone uptake. In the placebo group, scores remained unchanged.

“We don’t have enough people in the study to make any definitive statement about cognition, but it’s nice to see the trend going in the right direction, Dr. Cunnane said. “I really think of this as a dose-finding study and a chance to demonstrate the safety and tolerability of a liquid MCT supplement in people with MCI. Our next study will use a 45 g per day supplement of MCT.”

Details of the KDRAFT study

The BENEFIC study looked only at the effects of an MCT supplement, which may not deliver all the metabolic benefits of a ketogenic diet. KDRAFT, however, employed both, and assessed not only cognitive outcomes and adverse effects, but the practical matter of whether AD patients and their caregivers could implement the diet and stick to it.

Couples recruited into the trial met with a dietitian who explained the importance of sticking with the strict fat:carb:protein ratio. It’s not easy to stay in that zone, Dr. Swerdlow said, and the MCT supplement really helps there.

“Adding the MCT, which is typically done for the ketogenic diet in epilepsy, increases the fat intake so you can tolerate a bit more carbohydrate and still remain in ketosis. MCT therefore makes it easier to successfully do the diet, if we define success by time in ketosis. Ultimately, it is an iterative diet. You check your urine, and if you are in ketosis, you are doing well. If you are not in ketosis, you have to increase your fat intake, decrease your carb intake, or both.”

The study comprised 15 patients (7 with very mild AD, 4 with mild, and 4 with moderate disease). All patients were instructed to remain on their current medications for Alzheimer’s disease for the duration of the study if they were taking any. All of the patients with moderate AD and one with very mild AD dropped out of the study within the first month, citing caregiver burden. The supplement was in the form of an oil, not an emulsion like the BENEFIC supplement, and it caused diarrhea and nausea in five subjects, although none discontinued because of that.

“We found that a slow titration of the oil could deal with the GI issues. Rather, the primary deal-breaker seemed to be the stress of planning the menus and preparing the meals.”

One patient discontinued his cholinesterase inhibitor during the study, for unknown reasons. His cognitive scores declined, but was still included in the diet-compliant analysis.

The diet didn’t affect weight, blood pressure, insulin sensitivity or resistance, or glucose level, but the intervention was short-lived. Nor were there any significant changes in high-density, low-density, or total cholesterol. Liver enzymes were stable, too.

“The only thing that changed was that they really did increase their fat and decrease their carb intake,” Dr. Swerdlow said. Daily fat jumped from 91 g to 167 g, and carbs dropped from 201 g to 46 g.

Almost everyone who stuck with the diet achieved and maintained ketosis during the study, although with varying degrees of success. “Many only had a trace amount of urinary ketones,” Dr. Swerdlow said. The investigators tracked serum beta hydroxybutyrate levels every month as well, and those measures also confirmed ketosis in the group as a whole, although some patients fluctuated in and out of the state.

The cognitive changes were striking, he said. In the 10-patient analysis, ADAS-cog scores improved by an average of 4.1 points. The results were better when Dr. Swerdlow excluded the patient who stopped his cholinesterase inhibitor medication. In that nine-patient group, the ADAS-cog improved an average of 5.3 points.

While urging caution over the small sample size and lack of a control comparator, Dr. Swerdlow expressed deep satisfaction over the outcomes. A clinician as well as a researcher, he is accustomed to the slow but inexorable decline of AD patients.

“I’m going to try to relate the impression you get in the clinic with these scores,” he said. “Very rarely, but sometimes, with a cholinesterase inhibitor in patients, we’ll see something like a 7-point change. That’s a fantastic response, an improvement you can see across the room. A change of 2 points really doesn’t look that much different, although caregivers will tell you there is a subtle change, maybe a little more focus. The average we got in our 10 subjects was a 4-point improvement. That’s impressive. And a 5-point change is like rolling the clock back by a year.”

The improvements didn’t last, though. A 1-month washout period followed the intervention. By the end, both ADAS-cog and Mini-Mental State Examination scores had returned to their baseline levels. At the end of the study, a few of the patients and their partners expressed their intent to resume the diet, but the investigators do not know whether this indeed happened. Still, the results are encouraging enough that, like Dr. Cunnane, Dr. Swerdlow hopes to conduct a larger, longer study – one that would include a control group.

Future investigations of the ketogenic diet in AD might do well to also include an exercise component, both researchers mentioned. In addition to starvation, ketogenic dieting, and MCT supplementation, exercise is an effective way to induce ketogenesis.

“Exercise produces ketones, but most importantly, it increases the capacity of the brain to use ketones,” Dr. Cunnane said. The connection may help explain some of the cognitive benefits seen in exercise trials in patients with MCI and AD.

“This raises the possibility that if in fact exercise benefits the brain, ketone bodies may mediate some of that effect,” Dr. Swerdlow said. “Could exercise potentiate the ketosis from the diet? That is possible, and maybe using these interventions in conjunction would be synergistic. At this point, we are just happy to show the diet is feasible, if even for a limited period.”