| アブストラクト | BACKGROUND: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are potent lipid-lowering therapies, however, concerns regarding their neurocognitive safety persist because of conflicting evidence. METHODS: We applied an integrated approach combining real-world pharmacovigilance, genetic epidemiology, and preclinical models. Disproportionality analysis was performed using the FDA Adverse Event Reporting System (FAERS) data to assess cognitive adverse events. Two-sample Mendelian randomization (MR) was used to assess the causal effects of apolipoprotein B (ApoB) lowering and PCSK9 inhibition on Alzheimer's disease (AD) using UK Biobank and FinnGen data, with a factorial MR design to evaluate interactions stratified by ApoB and PCSK9 polygenic risk. Preclinically, hepatocyte-specific knockout and pharmacological inhibition of PCSK9 in AD-transgenic mice were assessed through cognitive testing and neuropathological assessment. RESULTS: FAERS analysis showed no increased reporting signal for cognitive adverse events with PCSK9 inhibitors. For AD, the ROR was below unity (ROR = 0.62, 95% CI 0.45-0.87), whereas no statistically significant signal was observed for dementia (ROR = 0.92, 95% CI 0.79-1.08). In contrast, statins showed significant disproportionality signals for AD (ROR = 2.86, 95% CI 2.51-3.26) and dementia (ROR = 1.51, 95% CI 1.36-1.67). MR analysis revealed no causal association between genetically proxied PCSK9 inhibition and AD risk (OR = 1.00, 95% CI 0.93-1.07), or between ApoB and AD risk (OR = 0.79, 95% CI 0.56-1.11). In AD-transgenic mice, PCSK9 knockout reduced low-density lipoprotein-cholesterol by 54% without impairing cognition or neuronal integrity, or increasing amyloid-beta plaques and astrocytes. Pharmacological inhibition of PCSK9 similarly showed no cognitive deficits. CONCLUSIONS: Integrated evidence from pharmacovigilance, genetic epidemiology, and preclinical models robustly supports the neurocognitive safety of PCSK9 inhibitors, including in individuals with high ApoB levels. These findings affirm their long-term neurocognitive safety profile in the management of atherosclerotic cardiovascular disease. |
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| 組織名 | Department of Basic Innovation Research, Beijing Hospital, National Center for;Gerontology; National Clinical Research Center for Gerontology; The Key;Laboratory of Geriatrics of NHC; Beijing Key Laboratory of Aging Mechanism and;Intervention Research on Aging-Related Diseases; Institute of Geriatric Medicine,;Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1, Dahua;Road, Dongdan, Beijing, 100730, Dongcheng District, P. R. China.;Precision Medicine Center, Gut Microbiome Diagnosis and Treatment Center,;Chongqing Municipality Clinical Research Center for Geriatrics and Gerontology,;The Second Affiliated Hospital of Chongqing Medical University, Chongqing,;400010, PR China.;Clinical Research Center, The Third Xiangya Hospital, Central South University,;138 Tongzipo Road, Changsha, 410013, P. R. China.;Peking University Fifth School of Clinical Medicine, Beijing, 100730, P. R.;China.;138 Tongzipo Road, Changsha, 410013, P. R. China. luyao0719@163.com.;Department of Cardiology, The Third Xiangya Hospital of Central South University,;Changsha, 410013, Hunan, P. R. China. luyao0719@163.com.;Department of Bariatric and Metabolic Surgery, The Third Xiangya Hospital of;Central South University, 138 Tongzipo Road, Changsha, 410013, Hunan, P. R.;China. luyao0719@163.com.;China. zly8128@csu.edu.cn.;Furong Laboratory, Central South University, Changsha, 410013, Hunan, P. R.;liguoping4195@bjhmoh.cn. |
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