PCSK9 Variants, LDL-Cholesterol, and Neurocognitive Impairment: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Background—Despite concerns about adverse neurocognitive events raised by prior trials, pharmacologic PCSK9 inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in life-long exposure to low LDL-C can provide information on the potential long-term effects of low LDL-C on neurocognitive impairment and decline.
Methods—We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among African-American REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants with (n=241) and without (n=10,454) C697X or Y142X LOF variants. Neurocognitive tests included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, Delayed Recall, Animal Fluency) and Six Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥ 1.5 standard deviations (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 (ORs) for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% 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, 0.20) and -0.07 (95% CI -0.18, 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). ORs for neurocognitive impairment per 20 mg/dL LDL-C 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 life-long exposure to low PCSK9 levels and cumulative exposure to lower LDL-C are not associated with neurocognitive effects in African Americans.
- Received June 9, 2017.
- Revision received October 16, 2017.
- Accepted October 30, 2017.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License (http://creative commons.org/licenses/by-nc/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.