A study looking at people with genetic variants that mimic the effect of statins and PCSK9 inhibitors showed significantly worse cognition and brain area among those with the statin variants. This suggests that statins may negatively impact the brain (PMID 35953131).

This suggests that important benefits to cerebrovascular disease may be counterbalanced by other negative effects on the brain by statins through other mechanisms.

An important caveat to the study is that while these statin-mimicking variants are expressed everywhere in the body in people who have inherited them, different statins have a different degree of selectivity for the liver versus other tissues (such as the brain).

Statins that are selective for the liver are called hydrophilic, while those that are nonspecific and inhibit HMGCR in all tissues (including the brain) are called lipophilic.

This is because lipophilic statins freely travel across cell membranes, while hydrophilic statins need to be transported into liver cells using transporters (OATP1B1, OATP1B3, OATP2B1, BCRP, and MRP2) expressed only in the liver (PMID: 29051147).

Interestingly, another recent study found that statin users with mild cognitive impairment using lipophilic statins had an increased risk of converting to dementia compared to non-users and users of hydrophilic statins (https://jnm.snmjournals.org/content/62/supplement_1/102).

This same study found using FDG PET a decline in metabolism in several regions of the brain important for cognition in those using lipophilic statins but not non-users or users of hydrophilic statins.

While no strong, gold standard evidence implicates lipophilic statins as harmful for brain health, given the wide availability of similarly priced alternatives, these findings might suggest that hydrophilic statins should be preferred to lipophilic ones whenever possible. 

The hydrophilic statins are pravastatin (Pravachol) and rosuvastatin (Crestor), while the lipophilic statins are fluvastatin (Lescol), lovastatin (Mevacor, Altoprev), simvastatin (Zocor), atorvastatin (Lipitor), and pitavastatin (Livalo).

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