Physicians' Academy for Cardiovascular Education

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

Literature - Mefford MT, Rosenson RS, Cushman M, et al. - Circulation 2017; published online ahead of print


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 [4]. 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.

Main results


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.


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