Background: Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline.

Methods: We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10 454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests.

Results: The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58–2.13) using the CERAD battery and 0.89 (95% CI, 0.61–1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1–9.1) study period ranged between 0.07 (95% CI, −0.06 to 0.20) and −0.07 (95% CI, −0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P>0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96–1.08) and 0.99 (95% CI, 0.95–1.02) for the CERAD and SIS definitions of impairment, respectively.

Conclusions: These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.

背景：尽管担心先前试验引起不良的神经认知事件，但在最近的一项3期随机试验中，药理学PCSK9（前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型）抑制作用与神经认知作用无关。PCSK9功能丧失（LOF）变体导致终身暴露于较低水平的低密度脂蛋白胆固醇，可以提供有关较低的低密度脂蛋白胆固醇对神经认知损害​​和衰退的潜在长期影响的信息。

方法：我们调查了有（n = 241）和没有（n = 10 454）C697X或Y142X LOF变体的黑人REGARDS研究（卒中的地理和种族差异原因）参与者中PCSK9 LOF变体与神经认知损害​​和衰退之间的关联。神经认知测试包括建立阿尔茨海默氏病注册机构联盟（单词列表学习，世界列表延迟召回，语义动物流利性）和六项筛选（SIS）评估，这些评估是在随访期间纵向进行的。神经认知障碍的定义是在2或3次CERAD评估中年龄，性别和基于教育的特定于阶层的平均分低于≥1.5 SD，或者在基线或随访期间，任何SIS评估分别低于5分。

结果：平均样本年龄为64岁（SD，9岁），女性为62％，根据CERAD和SIS定义，在任何评估中，神经认知障碍的患病率分别为6.3％和15.4％。使用CERAD电池对有和没有PCSK9 LOF变异的参与者进行神经认知损害​​的校正比值比为1.11（95％置信区间[CI]，0.58–2.13），而使用SIS评估，为0.89（95％CI，0.61-1.30）。参与者在5.6年（0.1-9.1）范围内的单个神经认知评估得分的标准化平均差异介于0.07（95％CI，-0.06至0.20）和-0.07（95％CI，-0.18至0.05）之间有无PCSK9 LOF变体。有和没有PCSK9 LOF变异的参与者之间的神经认知衰退模式相似（所有P> 0.10）。对于CERAD和SIS损伤定义，每20 mg / dL低密度脂蛋白胆固醇降低的神经认知损伤的几率分别为1.02（95％CI，0.96-1.08）和0.99（95％CI，0.95-1.02）。

结论：这些结果表明，终身接触低水平PCSK9和累积接触较低水平的低密度脂蛋白胆固醇与黑人的神经认知作用无关。