Ketogenesis and Alzheimer’s disease

 

Under normal circumstances, glucose is the main energy substrate for the brain. Alzheimer’s disease is characterized by early and region-specific declines in cerebral glucose metabolism. The body produces ketones (β-hydroxybutyrate (BHB), acetoacetate (ACA) and acetone) during glucose deprivation, and they are metabolized by the brain. The researchers for this study wanted to determine whether administering an oral ketogenic compound, AC-1202, to patients with probable Alzheimer’s disease could improve cognitive performance.1

 

There were statistically significant cognitive effects administration of the ketogenic compound for the participants who were APOE4 negative. In each analysis, significant change from baseline cognitive scores (ADAS-Cog scores) compared to placebo were found in APOE4 negative subjects, at both Day 45 and Day 90, and the significant effects on APOE4 negative subjects was lost after the two week washout period (Day 90-104 where no treatment or placebo is administered). The researchers concluded that chronic induction of ketosis may offer a treatment strategy for this subgroup of Alzheimer’s disease patients, which can be used in conjunction with other therapies.

 

AC-1202 is a medium chain triglyceride (MCT) composed of glycerin and caprylic acid. The AC-1202 MCT for this study was NeoBee 895®, which is a common food ingredient, made using glycerin from vegetable oil and fatty acids from coconut or palm kernel oil. The mixture contained 33% AC-1202.

The 90-day, randomized, double-blind, placebo-controlled, parallel-group study was conducted with 152 patients who were diagnosed with mild to moderate Alzheimer’s disease. Participants in the study were scheduled for five visits: screening, baseline, and days 45, 90 and 104 (+3 days). The patients were screened for eligibility (outpatient, mild to moderate Alzheimer’s disease diagnosis, inclusive Mini-Mental State Examination (MMSE) score between 14 and 24, Modified Hachinski Ischemia Scale score <4, and an MRI or CT within the prior 24 months that showed no tumors) at one of 23 clinical sites within the United States. Patients were excluded if they exhibited major depression (determined by score of >13 on the Cornel Scale for Depression in Dementia), hypothyroidism, clinically significant B12 deficiency within 12 months prior to the baseline measure, clinically-significant renal or hepatic disease or insufficiency, or any type of diabetes.

The patients were on a normal diet, continued taking their approved Alzheimer’s disease medications, and received a daily dose of AC-1202 or placebo. The AC-1202 and placebo in this study were administered as a powder that was mixed into 8oz of water, juice, or milk before being given to the patient. Later, the instructions were changed to include a meal replacement drink, such as Ensure, to help tolerability of the AC-1202.

For the first 7 days, the patients received one 30gm sachet daily of either AC-1202 or the placebo. From day 8 to day 90, patients received two 30gm sachets daily. The AC-1202 mix and placebo were given at breakfast on all days except clinic visits days. On clinic visit days, the sachets were administered at the clinic and the patients ate breakfast prior to their arrival at their appointment.

Baseline and end cognitive measures were evaluated using the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study-Clinical Global Impression of Change (ADCS-OGIC). The AC-1202 levels were compared to placebo values in several population groups, including: intention to treat, per protocol, and dosage compliant groups. The results for the study were stratified by whether the patient carried the APOE4 allele.

Baseline characteristics for the placebo group and AC-1202 treatment group were well matched for age, height, weight and gender, and both groups were also comparable for baseline MMSE and ADAS-Cog scores. 78.7% of the AC-1202 treatment group and 83.3% of the placebo group were taking currently approved Alzheimer’s disease medications. The proportion of subjects taking more than one Alzheimer’s disease medication was higher among Placebo group (36.4%) than among AC-1202 treatment group (27.9%). Of the participants that completed genotyping, fifty-six percent were APOE4 positive (n = 69, 55.6%), and forty-four percent were APOE4 negative (n = 55, 44.4%). The APOE4 positive and APOE4 negative participants were not significantly different in age, sex, baseline ADAS-Cog, or baseline MMSE.

The protocol became difficult for many of the patients. All of the 152 patients received at least one dose of the AC-1202 mixture or the placebo (86 AC-1202, 66 Placebo). After notifying the researchers, they were allowed to interrupt or reduce their dose if necessitated by adverse events. Patients in the placebo group received higher cumulative doses and remained on-study for a longer period of time than did subjects receiving AC-1202. The AC-1202 group received a median dose of 83.9% of the intended dose over the 90 days of the intervention, while the placebo group received a median dose of 95.7% of the intended dose over the same time period.

To evaluate ketone levels, beta-hydroxybutyrate (BHB) was measured. BHB levels, at the beginning of the study, were within normal ranges and did not differ between the AC-1202 and placebo groups. Treatment of AC-1202 resulted in significantly elevated BHB levels at all post-dose assessments. At baseline, patients in the AC-1202 treatment group received 1/2 the dose of AC-1202 that they would get later (one sachet) and mean serum BHB increased from 0.09 mM at pre-dose, to 0.14 mM 2 hours post-dose, which was significantly different from the placebo group. Researchers measured higher post-dose levels of BHB on Day 45 and Day 90 when patients were given a full dose (two sachets of AC-1202). Average post-dose BHB values in the AC-1202 treatment group were 0.36 mM on Day 45 and 0.39 mM on Day 90, both significantly different from Placebo group. BHB levels were not different between AC-1202 and Placebo groups at any pre-dose sampling or after the 2 week washout visit.

Because AC-1202 has a unique metabolic pathway to other Alzheimer’s disease medications, participants were allowed to continue on stable Alzheimer’s disease treatments, with approximately 80% of the subjects in both groups were taking a form of Alzheimer’s disease therapy. Despite being tested in a population that was largely already undergoing other treatments, AC-1202 resulted in significant improvement in the ADAS-Cog test in APOE4 negative Alzheimer’s disease patients relative to placebo. The researchers concluded that chronic induction of ketosis may offer a treatment strategy for Alzheimer’s disease that can be used with other therapies.

  1. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC‐1202 in mild to moderate Alzheimer’s disease: a randomized, double‐blind, placebo‐controlled, multicenter trial. Nutrition and Metabolism (Lond). 2009; 6:31.

 

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