PCSK9 inhibitors do not increase cognitive risk.

Area of Science:

• Cardiovascular Disease Research
• Neuroscience
• Pharmacology

Background:

• Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are effective lipid-lowering drugs.
• Concerns about the neurocognitive safety of PCSK9 inhibitors exist due to conflicting evidence.

Purpose of the Study:

• To comprehensively evaluate the neurocognitive safety of PCSK9 inhibitors.
• To investigate the association between PCSK9 inhibition, apolipoprotein B (ApoB) levels, and neurodegenerative diseases like Alzheimer's disease (AD).

Main Methods:

• Integrated approach using real-world pharmacovigilance (FDA Adverse Event Reporting System - FAERS), genetic epidemiology (Mendelian randomization - MR), and preclinical models (AD-transgenic mice).
• Disproportionality analysis in FAERS data for cognitive adverse events.
• Two-sample and factorial MR using UK Biobank and FinnGen data to assess causal effects of PCSK9 inhibition and ApoB lowering on AD risk.
• Preclinical assessment in mice involving PCSK9 knockout and pharmacological inhibition, including cognitive testing and neuropathological evaluation.

Main Results:

• FAERS analysis revealed no increased reporting signal for cognitive adverse events with PCSK9 inhibitors; statins showed increased signals for AD and dementia.
• MR analysis indicated no causal association between genetically proxied PCSK9 inhibition or ApoB lowering and AD risk.
• Preclinical studies in AD-transgenic mice showed PCSK9 inhibition reduced LDL-C without cognitive impairment, neuronal damage, or increased amyloid-β pathology.

Conclusions:

• Integrated evidence robustly supports the neurocognitive safety of PCSK9 inhibitors.
• Findings affirm the long-term neurocognitive safety profile of PCSK9 inhibitors for managing atherosclerotic cardiovascular disease, even in individuals with high ApoB levels.