Review 2022. Of interest: genetic factors and differential impact of SNPs. Other points of interest impact of ethnicity on statin and drug combinations, periodontitis, cholesterol dependent and independent effects.
Statins and cognition: Modifying factors and possible underlying mechanisms
"Recently, a meta-analysis showed that statins have more cognitive benefits in APOE4 carriers and patients with higher cholesterol levels (Xuan et al., 2020). Similarly, in APOE4 carriers, a longitudinal study has found that statin use was associated with a slower rate of global cognition decline over 6 years compared with non-users in community-dwelling elderly Australians age 70–90 years. Meanwhile, in non-APOE4 carriers, the rate of memory or cognitive decline in long-delayed recall performance was similar between statin users and non-users (Samaras et al., 2019). Also, it has been reported that while the users of statins showed an increased risk of AD, only APOE4-carrier statin users displayed a slightly lower risk for AD and dementia, especially in men (Dagliati et al., 2020). Nevertheless, autopsy evidence of statin users in autopsy-confirmed Alzheimer’s dementia brains did not demonstrate a significant difference in any AD pathological neuroimaging markers, suggesting that the statin use neither improves nor worsens AD pathology according to their APOE4 status (Crum et al., 2018).
Several studies have indicated that single nucleotide polymorphisms (SNPs) can alter the pharmacokinetics of statins (Smiderle et al., 2016; Naito et al., 2017; Ahangari et al., 2020). For example, the genetic variant of the cytochrome P450 (CYP) family genes, encoding for the main enzymes of the hepatic metabolism of statins, can alter body exposure to statins, making patients more vulnerable to their effect on cognitive function (Schultz et al., 2018). It has been reported that the CYP2C19 polymorphism (rs4388808) confers protection against the Aβ burden in AD patients (Benedet et al., 2018). Besides, the gene encoding for CYP2C9 is linked to familial AD. CYP enzymes are also responsible for the metabolism of certain antihypertensive drugs, which are most often concomitantly used in older adults (Barthold et al., 2020), suggesting that some combinations of statins and antihypertensive drugs may alter the activity of CYP enzyme family and subsequently have a various effect on Alzheimer’s disease and related dementias (ADRD) risk. Consequently, the inconsistency among studies regarding the effects of statins on cognitive performance or memory impairment could be explained by differences in drug metabolism and transport (i.e., pharmacokinetic interactions between certain statins with other drugs and certain genetic variations of CYP enzymes) (Barthold et al., 2020). The effect of CYP polymorphisms on the cognitive effects of statins should be considered in future clinical trials as they can mask the outcomes of the analysis.
Moreover, the HMGCR gene polymorphisms can influence both the cholesterol-lowering response to statin and the pleiotropic statin protective effect on cognitive function (de Oliveira et al., 2022). It has been reported that rs3846662 might increase the HMGCR expression and thereby contribute to the onset and progression of AD (Ma et al., 2019). Conversely, rs17238484 was associated with a minor reduction in the risk of AD (Hon-Cheong et al., 2017). Additionally, a study conducted on three cohorts evaluated the association between AD and the HMGCR’s rs3846662 G negative status and highlighted that this variant was one of the most important protective genetic factors for AD, behind APOE2 (Leduc et al., 2015). However, Mendelian randomization analyses led on HMGCR did not suggest that the use of statins could alter AD risk (Williams et al., 2020). Finally, a pilot study showed that the genetic variants of CETP (Cholesteryl Ester Transfer Protein), rs5882-AA, and, the genetic variant of NR1H2 (Nuclear Receptor subfamily 1 group H member 2), rs2695121-CC, were associated with cognitive dysfunction, especially in patients using lipophilic statins. However, the effect of rs3846662 (HMGCR variant) had not been able to be evaluated (de Oliveira et al., 2022). More studies are needed to elucidate the exact effect of HMGCR gene polymorphisms in statin users."