Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial
Open accessAbstract
BACKGROUND: Alzheimer's disease (AD) is characterized by early and region-specific declines in cerebral glucose metabolism. Ketone bodies are produced by the body during glucose deprivation and are metabolized by the brain. An oral ketogenic compound, AC-1202, was tested in subjects with probable AD to examine if ketosis could improve cognitive performance. METHODS: Daily administration of AC-1202 was evaluated in 152 subjects diagnosed with mild to moderate AD in a US-based, 90-day, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were on a normal diet and continued taking approved AD medications. Primary cognitive end points were mean change from Baseline in the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC). AC-1202 was compared to Placebo in several population groups, including: intention-to-treat (ITT), per protocol, and dosage compliant groups. Results were also stratified by APOE4 carriage status (a predefined analysis based on the epsilon 4 (E4) variant of the apolipoprotein E gene). This trial was registered with ClinicalTrials.gov, registry number NCT00142805, information available at http://clinicaltrials.gov/ct2/show/NCT00142805 RESULTS: AC-1202 significantly elevated a serum ketone body (beta-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, N = 35). Furthermore, a significant pharmacologic response was observed between serum beta-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008). Adverse events occurred more frequently in AC-1202 subjects, were primarily restricted to the gastrointestinal system, and were mainly mild to moderate in severity and transient in nature. CONCLUSION: AC-1202 rapidly elevated serum ketone bodies in AD patients and resulted in significant differences in ADAS-Cog scores compared to the Placebo. Effects were most notable in APOE4(-) subjects who were dosage compliant.
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Treatment with a ketogenic agent improved cognitive functions in ApoE3 carriers but not in ApoE4 carriers.
“Treatment with a ketogenic agent improved cognitive functions in ApoE3 carriers but not ApoE4 carriers (Reger et al., 2004;Henderson et al., 2009), suggesting that ApoE genetic status affects brain ketone body utilization.”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Henderson et al., 2009
The Results (Effect of APOE4 status; page unavailable) report improved ADAS-Cog scores with AC-1202 in patients without APOE4, but no significant ADAS-Cog effect in APOE4 carriers. The paper stratified patients by APOE4 carriage, not APOE3 carriage, so it does not establish the claim specifically for all APOE3 carriers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE genetic status affects brain ketone body utilization.
“Treatment with a ketogenic agent improved cognitive functions in ApoE3 carriers but not ApoE4 carriers (Reger et al., 2004;Henderson et al., 2009), suggesting that ApoE genetic status affects brain ketone body utilization.”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Henderson et al., 2009
The Results (Effect of APOE4 status; page unavailable) report improved ADAS-Cog scores with AC-1202 in APOE4 non-carriers, but no significant effect in carriers. The Discussion proposes that genotype-related differences in ketone transport into the brain could explain this response, while explicitly calling the mechanism speculative. The trial did not directly measure brain ketone utilization, and its comparison was APOE4 non-carriers versus carriers, not specifically ApoE3 versus ApoE4 carriers. (LLM, conf=0.84)
Experimental — accuracy not yet measuredClinical studies have shown that treatment with a ketogenic agent improved cognitive performance in AD patients, but the therapeutic benefits appeared to be confined to ApoE4 noncarriers.
“Although clinical studies have shown that treatment with a ketogenic agent improved cognitive performance in AD patients, the therapeutic benefits appeared to be confined to ApoE4 noncarriers (Reger et al., 2004;Costantini et al., 2008;Henderson et al., 2009).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Henderson et al., 2009
In AD patients or patients with MCI, a ketogenic diet was associated with improvements in cognitive ability as assessed by the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog).
“In AD patients or patients with MCI, a ketogenic diet was associated with improvements in cognitive ability as assessed by the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog) [96]”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [96]
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- Authors
- Henderson, S. T., Vogel, J. L., Barr, L. J., Garvin, F., Jones, J. J., & Costantini, L. C.
- Affiliations
- Cerecin (Singapore) (SG)
- Corresponding author
- Henderson, Samuel T
- Venue
- Nutrition & Metabolism
- Published
- 2009
- Volume
- 6
- Issue
- 1
- Pages
- 31
- ISSN
- 1743-7075 (ISSN-L)
- PMC
- PMC2731764
- OpenAlex
- W2101304481
- Cited by
- 548
- References
- 69
- Citations by year
- 2026: 29 · 2025: 28 · 2024: 34 · 2023: 38 · 2022: 49 · 2021: 56 · 2020: 49 · 2019: 42 · 2018: 37 · 2017: 33 · 2016: 33 · 2015: 19 · 2014: 31 · 2013: 22 · 2012: 22
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nutrition & Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- University of Washington
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, ketone bodies, beta-hydroxybutyrate, ketogenic therapy, cognitive function, APOE ε4, brain glucose metabolism, ADAS-Cog, mild to moderate Alzheimer's disease, drug safety and tolerability, adverse events
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