Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
J Alzheimers Dis. 2022;87(1):359-372. doi: 10.3233/JAD-215735.
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.
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.
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.
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.
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.
他汀类药物对阿尔茨海默病（AD）临床变化的遗传效应可能是由胆固醇代谢相关遗传变异的上位性相互作用介导的。
研究 HMGCR（rs3846662）、NR1H2（rs2695121）或 CETP（rs5882&rs708272）与 AD 的认知和功能变化的相关性，根据 APOEɛ4 载脂蛋白状态和亲脂性他汀类药物的降脂治疗进行分层。
连续筛选出患有迟发性 AD 的门诊患者，通过认知测试进行筛查，同时护理人员对功能和总体评分进行评分，并对一年的神经递质变化进行前瞻性记录。
考虑到 n = 190：142 人患有高胆固醇血症，139 人使用亲脂性他汀类药物；次要等位基因频率分别为 rs2695121-T（46.3% 杂合子）、rs5882-G（49.5% 杂合子）和 rs708272-A（53.2% 杂合子），均处于 Hardy-Weinberg 平衡。对于 APOEɛ4 携带者：rs5882-GG 可预防认知能力下降；rs5882-AA 导致认知能力下降更快；rs2695121-CC 或 rs5882-AA 携带者更容易受到亲脂性他汀类药物的有害认知影响；rs5882-GG 或 rs708272-AG 携带者在使用亲脂性他汀类药物时具有功能益处。APOEɛ4 非携带者对亲脂性他汀类药物的任何认知或功能影响均有抵抗力，而 HMGCR 中 rs3846662 的不变性（均为 AA）阻止了对其效应的评估。仅评估 CETP 单倍型时：rs5882-GG 可预防认知和功能下降，无论是否使用亲脂性他汀类药物治疗；亲脂性他汀类药物通常会对 rs5882-A 和/或 rs708272-A 携带者的认知和功能造成损害；亲脂性他汀类药物可使 rs5882-G 和/或 rs708272-G 携带者的认知和功能受益。
据报道，CETP 和 NR1H2 的保护性变体也可减缓认知和功能下降，特别是对 APOEɛ4 携带者而言，且不论胆固醇变化如何，而亲脂性他汀类药物的治疗可能会影响特定遗传变异体的携带者。
