Some observational studies raised concern that statins may cause memory 
impairment, leading to a US Food and Drug Administration warning. Similar 
questions were raised regarding proprotein convertase subtilisin/kexin-type 9 
inhibitors (PCSK9i) and neurocognitive function. No prospectively designed study 
has evaluated the relationship between long-term PCSK9i use and cognition 
changes. Patients with prior cardiovascular disease treated with maximally 
tolerated statin enrolled in FOURIER (the randomized, double-blind, 
placebo-controlled cardiovascular outcome study of the PCSK9i evolocumab) could 
participate in this prospective assessment of cognitive function (EBBINGHAUS). 
Key additional exclusion criteria for EBBINGHAUS were dementia, cognitive 
impairment, or other significant mental or neurological disorder. Cognitive 
testing was performed using the Cambridge Neuropsychological Test Automated 
Battery, a tablet-based tool assessing executive function, working memory, 
memory function, and psychomotor speed at baseline, weeks 24 and 48, every 48 
weeks thereafter, and study end. The primary endpoint was spatial working memory 
strategy index of executive function (SWMSI). The primary hypothesis was that 
evolocumab would be noninferior to placebo in the mean change from baseline over 
time in SWMSI. Fifteen hundred cognitively normal patients completing the 
assessments provided approximately 97% power to demonstrate that the upper 95% 
confidence interval for the treatment difference in mean change from baseline in 
SWMSI over time is <20% of the SD of the mean change in the placebo group. An 
exploratory analysis will compare neurocognitive function in patients with 
post-baseline low-density lipoprotein cholesterol <25 mg/dL. EBBINGHAUS will 
evaluate whether the addition of evolocumab to statin therapy affects cognitive 
function over time in patients with stable cardiovascular disease.