Patients with Alzheimer’s disease enjoyed better daily function and quality of life on a ketogenic diet than a low-fat diet, a new study found, offering insight into brain metabolism and a possible new direction for treatment.

The paper, published Feb. 23 in Alzheimer’s Research & Therapy, was inspired by previous research into high-fat, low-carbohydrate diets for Alzheimer’s. Previous trials suggested that keto diets might enhance patients’ memory and cognition, but low adherence or the lack of a control group meant that scientists could only draw tentative conclusions. This study broke new ground, as it marks the first randomized trial of a keto diet for Alzheimer’s patients. Adherence was also high, as 21 out of the 26 patients stuck with the 12-week regimen.

Researchers are exploring keto diets because Alzheimer’s impairs glucose metabolism in the brain — some have even dubbed the disease “type III diabetes.” But an Alzheimer’s brain can still metabolize ketones, suggesting that diets which make the body burn more fat by inducing ketosis could provide more energy for thinking, memory and other neurological processes.

In addition, ketones stimulate the production of brain-derived neurotrophic factor, a protein involved in forming new synapses and nerves, and are a better source of fuel for the nervous system.

“The ketones are a more efficient energy molecule than glucose for cells – and of course, neurons would utilize that to the greatest extent, because they’re quite energy-demanding cells,” said Dr. Matthew C.L. Phillips, a neurologist at Waikato Hospital in New Zealand and lead author of the study.

Phillips and his colleagues relied on a randomized crossover design in which eligible participants were divided into two groups. One group ate a keto diet, while the other subsisted on a diet based on conventional low-fat, healthy-eating guidelines. Following a 10-week washout period, in which participants returned to their regular diets in order to eliminate the effects of either treatment, the group that initially ate the keto diet switched to a low-fat diet, and vice-versa.

Phillips acknowledged that the washout period was a challenge, especially when patients who adopted the keto diet started to improve. Participants were instructed to return to their usual diet, and the keto recipe booklets they had received were taken away. “You feel a bit bad, actually,” said Phillips. “I try to be objective and everything, but you can see some of these guys getting better. Yet one has to conduct the trial properly.”

According to the authors, two main factors helped participants stick with the keto diet. First, patients could choose from a variety of simple, inexpensive keto recipes, including some sweet desserts that previous research has shown Alzheimer’s patients tend to like.

“If we just gave them a straight-up ketogenic diet without some sweet-tasting options, I felt that adherence would be worse.” said Phillips. “The sweetness generally came from a natural sweetener called Natvia that we have widely available in New Zealand grocery stores.”

Second, patients used blood glucose and ketone monitors instead of manually recording the food they ate. This gave Phillips and his colleagues raw data on blood ketone levels, which confirmed that 18 of the 21 patients who stuck with the keto diet also entered physiological ketosis.

Assessors evaluated quality of life, daily function and cognition among the patients, testing and interviewing both patients and their trial partners, who were usually their spouses. Daily function and quality of life improved among keto dieters, while declining or remaining roughly the same among low-fat dieters. On the other hand, keto dieters showed no significant improvement in cognition.

The team took steps to ensure that assessors couldn’t tell what patients were eating. They prohibited any discussion of diet between assessors and either patients or trial partners — and because ketogenesis causes sweet-smelling acetone breath, the researchers concealed any giveaway aromas by putting a fragrance diffuser between participants and assessors.

“The idea came from criticism of an earlier study,” said Phillips, crediting a blogger who had covered his previous randomized control trial of a keto diet for Parkinson’s patients. “I’m thankful to that fellow now.”

Though larger than previous trials, this study was still relatively small, with only 26 total participants. In addition, the researchers did not blind participants to their diet. “That is just an unfortunate limitation of diet studies,” said Phillips. “We can never run a double-blinded diet study — it’s always going to be single-blinded.”

“We tried to get around that by playing up both of the diets,” Phillips continued, noting that participants received videos and emails praising whichever diet they were on as healthy.

The keto diet increased low-density lipoprotein, or LDL, and total cholesterol levels in the blood, the researchers noted, raising concerns about its implications for cardiovascular health.

Phillips believes the rise in LDL may be more complicated than it appears. Keto and fasting are believed to increase the large, buoyant kind of LDL particle, which does not seem to cause plaque formation in the arteries. Statins, on the other hand, may increase the small, dense kind of LDL particle implicated in plaque buildup, which is particularly worrying because they are the standard treatment for high cholesterol.

“We found most cardiovascular risk factors actually improved,” added Phillips, citing an increase in high-density lipoprotein and a decrease in glycated hemoglobin, a blood sugar biomarker used to diagnose diabetes.  

Phillips became interested in keto diets in 2012, after he finished his neurology training in Melbourne, Australia. He wanted to specialize in therapy, but there was no track for that in his field. “I took three years off where I worked and traveled in different places,” said Phillips. “Somehow I stumbled across these fasting and ketogenic diet approaches.”

“Stepping outside of the medical system allowed me to think much more broadly,” Phillips added. “I don’t think I could have done it if I’d just kept working.”

Phillips is also studying the efficacy of keto diets for treating cancer and Huntington’s disease.

Alzheimer’s affects tens of millions around the world, including over 5 million Americans. As the world’s population ages, the need for interventions against Alzheimer’s and other forms of dementia is only increasing. Phillips believes the keto diet may offer hope, though he emphasizes he does not recommend it as a frontline therapy.

“Although medications are useful, we may rely on them too much.” Phillips said, who noted that this trial was cheaper than conventional pharmaceutical trials. “They are good at alleviating certain disease symptoms but have limited effects beyond symptom control. By contrast, emerging evidence suggests that ‘metabolic therapies,’ such as fasting and ketogenic diets, may provide tangible benefits for whole-body metabolic health, which could be important given that many of today’s common disorders, such as cardiovascular disease, type 2 diabetes, cancer and Alzheimer’s, are characterized by defective metabolism.”

“If our goal is not just symptom control, but also to improve the health of the individual, then it is vital that we conduct much more research into metabolic therapies,” Phillips added. “We need to know whether they are effective against these disabling diseases — or not. Regardless of the answer, we need to know.”

The study, “Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease,” was published on Feb. 23 in Alzheimer’s Research & Therapy. The authors of the study were Matthew C.L. Phillips, Laura M. Deprez, Ruth Mylchreest, Linda J. Gilbertson, Karen M. Clark, Patricia V. Simpson, Eileen J. McManus, Jee-Eun Oh, Satish Yadavaraj, Beatriz Romero-Ferrando, Jan. A.C. Schepel, Stacey McCoy, Martijn Brinkhuis, Shah Samad, and Shenyang Liao, of Waikato Hospital, Grace M.N. Mortimer and Deborah K.J. Murtagh, of Healthy Kitchen Christchurch Ltd., Vanessa M. King, of LINC Mental Health Services, Avinesh Pillai, of the University of Auckland, and Bronwyn M. Copeland, of Tauranga Hospital.