Genetics
CETP haplotypes predict whether lipophilic statins help or harm cognition in Alzheimer's disease (J Alzheimers Dis 2022)
Original title: Pharmacogenetic Analyses of Therapeutic Effects of Lipophilic Statins on Cognitive and Functional Changes in Alzheimer's Disease
In 190 outpatients with late-onset Alzheimer's disease followed prospectively for one year, researchers examined whether HMGCR, NR1H2 or CETP (rs5882 and rs708272) variants were associated with cognitive and functional change, stratified by APOE-e4 status and lipophilic statin use. Among APOE-e4 carriers, the rs5882-GG genotype protected against cognitive decline while rs5882-AA was associated with faster decline, and carriers of rs5882-GG or rs708272-AG gained functional benefit from lipophilic statins. Considering CETP haplotypes alone, rs5882-GG protected against cognitive and functional decline regardless of statin therapy, lipophilic statins generally harmed cognition and function in carriers of rs5882-A and/or rs708272-A, and benefited carriers of rs5882-G and/or rs708272-G, indicating CETP genotype determines whether lipophilic statins help or harm cognitive outcomes in Alzheimer's disease.
Original abstract
Background: Pharmacogenetic effects of statins on clinical changes in Alzheimer's disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism.
Objective: To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOEɛ4 carrier status and lipid-lowering treatment with lipophilic statins.
Methods: Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year.
Results: Considering n = 190:142 had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOEɛ4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOEɛ4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G.
Conclusion: Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOEɛ4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.