Pharmacogenetics of Lipid Metabolism Modulators in Patients with Dementia Due to Alzheimer’s Disease (P5.223)

OBJECTIVE: To investigate whether polymorphisms of LDLR and CETP genes are associated with cognitive change in patients with dementia due to Alzheimer’s disease (AD) who have hyperlipidemia under treatment with statins or Ezetimibe. BACKGROUND: Genotypes of LDLR and CETP have been associated with risk of AD. It is unknown whether these genes may be associated with cognitive change in patients with AD. DESIGN/METHODS: Participants with late-onset AD according to National Institute on Aging - Alzheimer’s Association criteria were screened with Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Sum-of-Boxes (CDR-SB) and followed for one year. Genotyping was undertaken with TaqMan® Real-Time PCR technology for CETP polymorphisms I422V and TaqIB, and also for APOE, rs5930 (LDLR10), rs11669576 (LDLR8) and rs5925 (LDLR13). Presence of each polymorphism was correlated with APOE haplotypes and treatment using Simvastatin, Atorvastatin, Rosuvastatin and/or Ezetimibe. Mann-Whitney test and two-way ANOVA were employed for statistics, significance at ρ<0.05. RESULTS: A total of 141 consecutive patients were included, with minor allele frequencies of 0.06 (rs11669576), 0.36 (rs5930), 0.48 (rs5925), 0.37 (I422V) and 0.38 (TaqIB). Patients with the APOE-e4/e4 haplotype had earlier AD onset (ρ=0.008), particularly when the rs5930-AA genotype was also present (ρ=0.036). Patients with the I422V-AA genotype (ρ=0.004) or the rs5925-CC genotype (ρ=0.035) had later AD onset. Statins slowed the worsening of CDR-SB scores for patients with APOE4- haplotypes (ρ=0.004), particularly when they carried genotypes I422V-AA or I422V-AG (ρ=0.047). For carriers of APOE4+ haplotypes, statins slowed the worsening of MMSE scores when genotypes I422V-AA or I422V-AG were present (ρ=0.015), and slowed the worsening of CDR-SB scores when the haplotype rs11669576-GG : rs5925-TT was present (ρ=0.048). Statins also slowed the worsening of MMSE scores for non-carriers of the haplotype I422V-AA : TaqIB-AA (ρ=0.010), regardless of APOE haplotypes. Use of Ezetimibe was unrelated with cognitive change, regardless of any genotypes or haplotypes. CONCLUSIONS: Statins may slow cognitive decline for patients with AD who carry specific genetic profiles. Study Supported by: CAPES Disclosure: Dr. De Oliveira has received personal compensation for activities with Gerson Lehrman Group. Dr. Bertolucci has received personal compensation for activities with Novartis, Janssen Pharmaceutica, Eli Lilly & Company, Pfizer Inc., and Support. Dr. Smith has nothing to disclose. Dr. Chen has nothing to disclose.