Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial.
Level 2 - randomized trial
Individual randomized double-blind placebo-controlled trial
PubMed 19664276 · doi:10.1186/1743-7075-6-31
What was done
In a 90-day, US-based, multicenter, randomized, double-blind, placebo-controlled parallel-group trial (NCT00142805), 152 patients with mild-to-moderate Alzheimer's disease maintained their normal diet and standard medications while receiving daily oral AC-1202 (a ketogenic compound) or placebo. Primary endpoints were mean change from baseline on the ADAS-Cog cognitive scale and global scores on the ADCS-CGIC. Analyses were performed across intention-to-treat (ITT), per-protocol, and dosage-compliant cohorts, with predefined stratification by APOE4 allele carriage status.
What was found
AC-1202 significantly increased serum beta-hydroxybutyrate 2 hours post-dose compared to placebo. At Day 45, ADAS-Cog change favored AC-1202 in the ITT group (1.9-point difference, p = 0.0235), per-protocol group (2.53 points, p = 0.0324), and dosage-compliant group (2.6 points, p = 0.0215). In APOE4-negative participants, differences favoring AC-1202 were larger and sustained through Day 90: in the ITT cohort (n = 55), differences were 4.77 points at Day 45 (p = 0.0005) and 3.36 points at Day 90 (p = 0.0148); in dosage-compliant APOE4-negative participants, differences were 6.26 points at Day 45 (p = 0.0011, n = 38) and 5.33 points at Day 90 (p = 0.0063, n = 35). Serum beta-hydroxybutyrate levels correlated with ADAS-Cog improvements at Day 90 in APOE4-negative subjects (p = 0.008). Adverse events were more frequent with AC-1202, primarily mild-to-moderate, transient gastrointestinal symptoms. Specific numeric results for the ADCS-CGIC or Day 90 overall ITT cohort were not reported in the abstract.
Why it matters
This study shows that induced ketosis via an oral compound can acutely improve cognitive scores in Alzheimer's disease, but reveals a substantial pharmacogenetic divergence where benefits appear restricted to non-APOE4 carriers.
Limits
The intervention period was short (90 days) with a modest overall sample size and small subgroup sizes (35 to 55 per APOE4-negative subgroup). No significant benefit was reported for APOE4 carriers. The abstract does not report numerical findings for the co-primary ADCS-CGIC outcome or Day 90 cognitive scores for the full sample.
Cited by
- supports A clinical trial evaluating the caprylic triglyceride supplement AC-1202 in Alzheimer's disease found cognitive improvements correlated with ketone levels, but this correlation was absent in APOE4 carriers.
- supports In Accera's clinical trial of AC-1202 (tricaprylin/MCT), ApoE4-positive Alzheimer's disease patients were non-responsive to hyperketonemia compared to ApoE4-negative patients.