Effects of genetic PCSK9 or HMG-CoA reductase inhibition on cognitive function
Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function
Introduction and methods
As PCSK9 is known to affect development of the central nervous system, neurodifferentiation, and neuronal apoptosis, inhibiting this important LDL-c regulator may impact brain functions [1-3]. However, the long-term effects of PCSK9 inhibition on neurocognitive outcomes have not been studied. In addition, research on the association of statin use with cognitive impairment and/or dementia has yielded conflicting results [4,5].
Aim of the study
The study aim was to evaluate the relationships of long-term PCSK9i or statin use with detailed neurocognitive outcomes.
The authors used recently released, publicly available, summary-level data from genome-wide association studies on LDL-c levels (∼740,000 participants of predominantly European ancestry in combined sample) and extracted single-nucleotide polymorphisms within or near the genes for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9. They performed drug-target Mendelian randomization (MR) on neurocognitive phenotypes related to general cognitive function and dementia. Drug-target MR analyzes genetic variants that simulate the pharmacological inhibition of drug target gene and is used to strengthen the causal inference regarding the potential impact of these drug target genes. The specific effect of PCSK9 inhibition, independent of concomitant drugs such as statins, was estimated.
The 7 cognitive function outcomes were: cognitive performance, fluid intelligence score, extremely high intelligence, memory performance, average reaction time, average cortical thickness, and total cortical surface area. The 4 dementia-related outcomes were: Alzheimer’s disease (AD) progression score, normalized hippocampal volume in AD, cerebral amyloid deposition in AD, and Lewy body dementia.
- Genetic PCSK9 inhibition had no significant effect on cognitive function.
- In contrast, genetic HMGCR inhibition was associated with lowered cognitive performance (beta=–0.082; 95%CI: –0.16 to –0.0080; P=0.03), slower reaction time (beta=0.00064; 95%CI: 0.00030–0.00098; P=0.0002), and reduced cortical surface area (beta=–0.18; 95%CI: –0.35 to –0.014; P=0.03).
- Neither PCSK9 nor HMGCR inhibition affected AD-related outcomes or risk of Lewy body dementia.
- The results were broadly consistent across the MR methods used, such as the Cochran’s Q test for heterogeneity, which strengthened the causal inference.
In these drug-target MR analyses, no genetic evidence was found for cognition-related side effects associated with PCSK9 inhibition, suggesting a neutral cognitive profile of PCSK9is. However, several neurocognitive effects related to HMGCR inhibition were identified, which indicated that continued pharmacovigilance of statins is critical. Yet, as the authors stress, “any potential adverse effects of HMGCR inhibition on neurocognition found in this study likely do not outweigh the cardiovascular benefits of statin use.”