Pharmacogenetic analysis of the effects of polymorphisms in APOE, IDE and IL1B on a ketone body based therapeutic on cognition in mild to moderate Alzheimer's disease; a randomized, double-blind, placebo-controlled study

Samuel T Henderson, Judes Poirier, Samuel T Henderson, Judes Poirier

Abstract

Background: To examine the effect of genetic variation in APOE, IDE and IL1B on the response to induced ketosis in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) in subjects with mild to moderate Alzheimer's disease (AD).

Methods: Genotype effects on ADAS-Cog scores from a randomized, double-blind, placebo-controlled study in mild to moderate AD were examined by an overall two way analysis of variance. In addition, interactions with the carriage status of the epsilon 4 allele of the APOE gene (APOE4) were examined.

Results: Significant differences in response to induced ketosis were found among non-carriers of putative gain-of-function polymorphisms in rs1143627 and rs16944 in the IL1B gene and among variants of the polymorphism rs2251101 in the IDE gene. Significant differences were found among non-carriers of the APOE4 gene, with notable improvement among the E3/E3 genotype group.

Conclusions: Variants in APOE, IL1B and IDE may influence the cognitive response to induced ketosis in patients with mild to moderate AD.

Trial registration: This trial was registered with ClinicalTrials.gov, registry number NCT00142805.

Figures

Figure 1
Figure 1
Subject Disposition.
Figure 2
Figure 2
Change from Baseline in ADAS-Cog scores among responder genotypes over time. Red markers represent mean change from Baseline among subjects administered AC-1202. Blue markers represent mean change from Baseline among subjects administered Placebo. Error bars represent standard error of the mean. A Solid lines and solid markers represent subjects who are APOE4(-). Dotted lines and solid markers represent mean scores of subjects who are heterozygous for the IDE SNP rs2251101. Dashed lines and open markers represent mean scores of subjects who were E4(-) and heterozygous for the IDE SNP rs2251101. B Solid lines and solid markers represent subjects who are APOE4(-). Dotted lines and solid markers represent mean scores of subjects who are homozygous for the IL1B SNP rs1143627 T allele. Dashed lines and open markers represent mean scores of subjects who were E4(-) and homozygous for the IL1B SNP rs1143627 T allele. Asterisks represent significant difference between AC-1202 and Placebo means (p-value < 0.05).
Figure 3
Figure 3
A model of genotypic effects on ketone body metabolism in mild-to-moderate Alzheimer's disease. Non-carriers of the APOE4 allele may have decreased insulin signaling allowing for increased ketone body metabolism. Carriers of the T allele of rs2251101 have elevated Ide activity relative to C carriers and therefore reduced insulin signaling. Carriers of the rs1143627 T and rs16944 C alleles have a reduced inflammatory response relative to rs1143627 C and rs16944 T carriers. This reduced inflammatory response may allow for improved ketone body metabolism. Each of the polymorphisms that reduce insulin signaling may allow for better response to induced ketosis in AD.

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