Pharmacogenetic Analyses of Therapeutic Effects of Lipophilic Statins on Cognitive and Functional Changes in Alzheimer's Disease

Author(s)

de Oliveira, Fabricio Ferreira ; Ferreira Bertolucci, Paulo Henrique ; Chen, Elizabeth Suchi ; Smith, Marilia Cardoso

• Document type: Journal article
• Source: JOURNAL OF ALZHEIMER'S DISEASE; v. 87, n. 1, p. 14-pg., 2022-01-01.

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 APOE epsilon 4 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 APOE epsilon 4 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. APOE epsilon 4 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 APOE epsilon 4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants. (AU)

• FAPESP's process: 15/10109-5 - Comparative analysis of cerebrospinal fluid and serum markers in dementia with Lewy Bodies and Alzheimer's Disease dementia
• Grantee: Fabricio Ferreira de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral