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

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.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.Variants in APOE, IL1B and IDE may influence the cognitive response to induced ketosis in patients with mild to moderate AD.This trial was registered with ClinicalTrials.gov, registry number NCT00142805.Alzheimer's disease (AD) is a progressive neurodegenerative disease. The major risk factors for the most common form of AD, known as late onset or sporadic AD, are age and possession of one or more copies of the epsilon 4 variant of the apolipoprotein E gene (APOE4). APOE4 behaves in a dominant dose-dependent manner. One copy of APOE4 increases the risk of developing AD by about 3 fold, while two copies increases the risk approximately 10 fold [1,2].Alzheimer's disease is characterized by an early and progressive decrease in the cerebral metabolic rate of glucose (CMRglc) [3-5]. The primary regions affected in AD are the posterior cingulate and the parietal, temporal, and prefrontal cortices. These regions correlate with the highly metabolically active default network, suggesting a metabolic link between hypometabolism, amyloid deposition, and cell atrophy (for review see [6]). The declines in CMRglc in AD could be attributed to loss of cells or synaptic fields, however, decreased rates of glucose phosphorylation [7] and low expression of energy generating genes [8] have been observed in AD, suggesting an underlying metabolic