Mitchell Center for Neurodegenerative Disorders, Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA.
Pharmacology and Toxicology Graduate Program, University of Texas Medical Branch, Galveston, TX, USA.
J Alzheimers Dis. 2023;95(2):585-597. doi: 10.3233/JAD-230526.
Evidence suggests patients prescribed calcineurin inhibitors (CNIs) have a reduced prevalence of dementia, including Alzheimer's disease (AD); however, this result has never been replicated in a large cohort and the involved mechanism(s) and site of action (central versus periphery) remain unclear.
We aim to determine if prescription of CNIs is associated with reduced prevalence of dementia, including AD, in a large, diverse patient population. Furthermore, we aim to gain insight into the mechanism(s) and site of action for CNIs to reduce dementia prevalence.
Electronic health records (EHRs) from patients prescribed tacrolimus, cyclosporine, or sirolimus were analyzed to compare prevalence, odds, and hazard ratios related to dementia diagnoses among cohorts. EHRs from a random, heterogeneous population from the same network were obtained to generate a general population-like control.
All drugs examined reduced dementia prevalence compared to the general population-like control. There were no differences in dementia diagnoses upon comparing tacrolimus and sirolimus; however, patients prescribed tacrolimus had a reduced dementia prevalence relative to cyclosporine.
Converging mechanisms of action between tacrolimus and sirolimus likely explain the similar dementia prevalence between the cohorts. Calcineurin inhibition within the brain has a greater probability of reducing dementia relative to peripherally-restricted calcineurin inhibition. Overall, immunosuppressants provide a promising therapeutic avenue for dementia, with emphasis on the brain-penetrant CNI tacrolimus.
有证据表明，接受钙调神经磷酸酶抑制剂（CNI）治疗的患者痴呆症（包括阿尔茨海默病，AD）的患病率较低；然而，这一结果从未在大型队列中得到复制，并且涉及的机制和作用部位（中枢与外周）仍不清楚。
我们旨在确定在大型、多样化的患者群体中，CNI 的处方是否与痴呆症（包括 AD）的患病率降低有关。此外，我们旨在深入了解 CNI 降低痴呆症患病率的作用机制和作用部位。
分析接受他克莫司、环孢素或西罗莫司治疗的患者的电子健康记录（EHR），以比较不同队列中痴呆症诊断的患病率、比值比和风险比。从同一网络中随机、异质的人群中获取 EHR，以生成一般人群样本来进行对照。
与一般人群样对照相比，所有检查的药物都降低了痴呆症的患病率。他克莫司和西罗莫司比较，痴呆症诊断无差异；然而，与环孢素相比，接受他克莫司治疗的患者痴呆症患病率降低。
他克莫司和西罗莫司之间的作用机制趋同可能解释了队列之间相似的痴呆症患病率。大脑内的钙调神经磷酸酶抑制比外周限制的钙调神经磷酸酶抑制更有可能降低痴呆症的发生。总体而言，免疫抑制剂为痴呆症提供了有前途的治疗途径，重点是具有脑穿透性的 CNI 他克莫司。
