Does lowering LDL-C impact cognition in adults?
"Does lowering circulating LDL-C with PCSK9i have similar detrimental cognitive effects? As I discussed in my original post, mounting evidence indicates that the answer is no.
In separate randomized controlled trials for alirocumab and evolocumab, both drugs were found to yield significantly greater reductions in LDL-C and total serum cholesterol than placebo treatment among high CV-risk adult subjects.
For both studies, neurocognitive function was examined using the Cambridge Neuropsychological Test Automated Battery (CANTAB), a series of modules used extensively in research to assess memory, attention, reasoning, and coordination.
Treatment vs. placebo groups exhibited no significant differences in neurocognition across any of the CANTAB modules.
Further, investigators behind the evolocumab trial also conducted analyses in which the groups were stratified by lowest-attained LDL level over the intervention period. By doing so, they demonstrated the absence of any correlation between lowest-attained LDL-C level and CANTAB performance, indicating that even very low LDL-C levels do not impact cognition.
So now we reach the question of the hour: does PCSK9 inhibition impair cognition in the developing brains of adolescents? Fortunately, this question also occurred to the authors of the recent HAUSER-RCT study, who then sought to investigate. Subjects aged 10-17 with familial hypercholesterolemia (FH) were treated with either placebo or the PCSK9i evolocumab for 24 weeks, after which they were tested for cognitive function in four domains: psychomotor function, attention, executive function, and visual learning. As seen in adult trials, evolocumab treatment did not result in cognitive decline relative to either baseline measurements or to the placebo group in any of the domains tested.
So now we reach the question of the hour: does PCSK9 inhibition impair cognition in the developing brains of adolescents? Fortunately, this question also occurred to the authors of the recent HAUSER-RCT study, who then sought to investigate. Subjects aged 10-17 with familial hypercholesterolemia (FH) were treated with either placebo or the PCSK9i evolocumab for 24 weeks, after which they were tested for cognitive function in four domains: psychomotor function, attention, executive function, and visual learning. As seen in adult trials, evolocumab treatment did not result in cognitive decline relative to either baseline measurements or to the placebo group in any of the domains tested.
So now we reach the question of the hour: does PCSK9 inhibition impair cognition in the developing brains of adolescents? Fortunately, this question also occurred to the authors of the recent HAUSER-RCT study, who then sought to investigate. Subjects aged 10-17 with familial hypercholesterolemia (FH) were treated with either placebo or the PCSK9i evolocumab for 24 weeks, after which they were tested for cognitive function in four domains: psychomotor function, attention, executive function, and visual learning. As seen in adult trials, evolocumab treatment did not result in cognitive decline relative to either baseline measurements or to the placebo group in any of the domains tested.
So now we reach the question of the hour: does PCSK9 inhibition impair cognition in the developing brains of adolescents? Fortunately, this question also occurred to the authors of the recent HAUSER-RCT study, who then sought to investigate. Subjects aged 10-17 with familial hypercholesterolemia (FH) were treated with either placebo or the PCSK9i evolocumab for 24 weeks, after which they were tested for cognitive function in four domains: psychomotor function, attention, executive function, and visual learning. As seen in adult trials, evolocumab treatment did not result in cognitive decline relative to either baseline measurements or to the placebo group in any of the domains tested.
The findings of these studies collectively suggest that LDL-C can be reduced even to very low levels without impacting the brain, but how is this possible when we know that cholesterol is so critical for neural development and function?
The reason is simple: why import what you can make yourself? Virtually every nucleated cell in the body is capable of synthesizing cholesterol, and the brain is no exception. In the CNS, cholesterol production exceeds demand, and net cholesterol flux is thus outward from the CNS across the blood-brain barrier. Indeed, measurements in experimental animals have found no evidence of plasma LDL particle uptake by the brain, indicating that systemic cholesterol has little, if any, effect on cholesterol supply in the CNS. In other words, although PCSK9i reduce circulating (serum) cholesterol, the brain remains unaffected because it doesn’t rely on serum cholesterol in the first place.
Children under age 5, for example, have very high demand for cholesterol in the brain yet have incredibly low serum cholesterol
(in the range of 20-50 mg/dL).
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