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

Abstract

BackgroundTo 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).MethodsGenotype 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.ResultsSignificant 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.ConclusionsVariants in APOE, IL1B and IDE may influence the cognitive response to induced ketosis in patients with mild to moderate AD.Trial registrationThis trial was registered with ClinicalTrials.gov, registry number NCT00142805.

Chemotherapy-Induced Neurotoxicity: Evidence of a Protective Role of CC Homozygosis in the Interleukin-1β Gene-511 C>T Polymorphism

“…The authors suggested that the known allelic presentation of the IL-1b gene is not a direct regulator of the IL-1b production, and conversely, the IL-1RA allele 2 is associated to an elevated IL-1b production in vitro (Santtila et al 1998). However, other authors described enhanced IL-1b circulating levels in vivo in patients with T allele at -511 position (El-Omar et al 2000;Hall et al 2004;Henderson and Poirier 2011). The protective effect of CC genotype of IL-1b-544 SNP in neurodegeneration has been already proposed by some authors (Licastro et al 2000;Green et al 2002;Di Bona et al 2008;Déniz-Naranjo et al 2008;Henderson and Poirier 2011).…”

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“…Clinical trials have shown an improvement in ADAS-COG score in AD patients after 90 days (Henderson & Poirier 2011), however this difference was only present in non-ε4 carriers.…”

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

“…For example, a trial of a medication which induced mild peripheral ketosis improved cognitive scores but only in E4 non-carrier participants. 105 These findings were not readily explained by differences in peripheral ketone body levels, and the authors speculated that the findings could be related to differences in brain transport of ketone bodies or their utilization.…”