PCSK9 LOF variants and low LDL-c levels not associated with neurocognitive impairment
PCSK9 Variants, LDL-Cholesterol, and Neurocognitive Impairment: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Data have suggested that PCSK9 inhibition is associated with neurocognitive adverse events. The EBBINGHAUS trial, however, has found no difference in change over time in neurocognitive function between participants randomized to evolocumab versus placebo on top of standard of care [1-3]. Exploring the possible association between PCSK9 loss-of-function (LOF) variants, which result in life-long exposure to low LDL-C, and neurocognitive function, may help understand these conflicting results.
The REGARDS study is a prospective cohort study that enrolled African-American and white adults ≥45 years of age between 2003 and 2007 . This analysis of the REGARDS study evaluated the association of PCSK9 LOF variants and LDL-C levels with neurocognitive impairment, for which only data of African-American participants were used (n=10,695). 241 participants (2.3%) had PCSK9 LOF variants.
Depressive symptoms were measured using the Center for Epidemiologic Studies Depression-4 (CESD-4) scale. For the assessment of neurocognitive impairment, participants completed at least one CERAD battery or SIS neurocognitive assessment during the course of the study. Neurocognitive impairment was defined as a score ≥1.5 SD below the stratum-specific mean on 2 or 3 of the verbal learning (WLL), memory (WLR), and semantic fluency (AF) tests from the CERAD battery. In a separate analysis based on SIS, neurocognitive impairment was defined as a score <5 during any assessment.
- Compared with participants without PCSK9 LOF variants, those with PCSK9 LOF variants had a higher prevalence of DM (35.5% vs 29.5%; P=0.05), a lower mean LDL-C (85 mg/dL vs 118 mg/dL; P<0.001), and a lower prevalence of statin use (13.3% vs 29.7%; P<0.001).
- Using the CERAD definition, the prevalence of neurocognitive impairment was 6.2% and 6.0% for individuals with and without PCSK9 LOF variants, respectively.
- Using the SIS definition, the prevalence of neurocognitive impairment was 15.2% in the PCSK9 LOF variants group and 15.7% in the group without PCSK9 LOF variants.
- In unadjusted models, the ORs for neurocognitive impairment comparing participants with vs. without PCSK9 LOF variants were 1.04 (95% CI: 0.54-1.98) with the CERAD definition and 0.97 (95% CI: 0.67-1.38) with the SIS definition. After full multivariable adjustment, the ORs for neurocognitive impairment were 1.11 (95% CI: 0.58-2.13) with the CERAD definition and 0.89 (95% CI: 0.61-1.30) with the SIS definition.
- In unadjusted models, the ORs for neurocognitive impairment per 20 mg/dL lower LDL-C were 1.05 (95% CI: 1.00 - 1.11) for the CERAD definition and 1.02 (95% CI: 0.99 - 1.05) for the SIS definition. After multivariable adjustment, the ORs for neurocognitive impairment were 1.02 (95% CI: 0.96 - 1.08) for CERAD and 0.99 (95% CI: 0.95 - 1.02) for SIS.
In a large prospective cohort of African-Americans, PCSK9 LOF variants and lower LDL-C levels were not associated with neurocognitive impairment. These results suggest that life-long exposure to low PCSK9 levels and the resulting low levels of LDL-C do not have major effects on neurocognitive outcomes.