Tasimelteon

Fanapt® Q2 2026 net product sales increased 23% to $36.0 million; total prescriptions increased 31% Full-year 2026 total revenue guidance of $240-$290 million Cash totaled $170.0 million as of June 30, 2026; expected to fund operations through at least the end of 2027 BYSANTI™ (milsaperidone) received FDA approval for bipolar I disorder and schizophrenia in Q1 2026; commercial launch expected in second half of 2026 Quimilza™ (imsidolimab) BLA for GPP under review by the FDA; PDUFA target action date of December 12, 2026 NEREUS™ for prevention of vomiting induced by motion became commercially available in Q2 2026 Results for three Phase III clinical trials expected by end of 2026: NEREUS™ (tradipitant) in vomiting in GLP-1, VQW-765 in social anxiety disorder HETLIOZ® (tasimelteon) in delayed sleep phase disorder WASHINGTON, Aug. 5, 2026 /PRNewswire/ -- Vanda Pharmaceuticals Inc. (Vanda) (Nasdaq: VNDA) today announced financial and operational results for the second quarter ended June 30, 2026. "We are pleased with the continued strong growth of Fanapt and the enthusiastic early response to NEREUS as it becomes available to patients. With BYSANTI approved and on track for launch in the second half of 2026, a December 2026 PDUFA date for Quimilza and multiple late-stage clinical trial results expected before year-end, we believe Vanda is well positioned for meaningful commercial expansion and pipeline value creation," said Mihael H. Polymeropoulos, M.D., Vanda's President, CEO and Chairman of the Board. "As our Phase III programs, launch preparations, and commercial supply manufacturing near completion, we expect operating expenses to begin moderating later this year and more significantly in 2027. Our current resources, together with anticipated product revenues, provide a solid foundation to advance our objectives through at least the end of 2027." Financial Highlights During 2025 and 2026, we have advanced multiple Phase III programs, continued execution on the commercialization of Fanapt® (iloperidone) and PONVORY® (ponesimod) and prepared for the commercial launches, including manufacturing commercial supplies, of NEREUS™ (tradipitant), BYSANTI™ (milsaperidone), and Quimilza™ (imsidolimab). These activities resulted in significantly increased operating expenses in 2025 and 2026. As these activities conclude, Vanda expects operating expenses to begin decreasing by the end of 2026 and more substantially throughout 2027. Based on its current cash position and anticipated revenues, Vanda expects to have sufficient resources to fund operations through at least the end of 2027. Second Quarter of 2026 Total net product sales were $50.5 million in Q2 2026, a 4% decrease compared to $52.6 million in Q2 2025. Total net product sales does not include approximately $7.0 million of HETLIOZ® revenue for orders shipped on June 29, 2026 that arrived on July 1, 2026. Fanapt® net product sales were $36.0 million in Q2 2026, up 23% year-over-year. HETLIOZ® (tasimelteon) net product sales were $5.6 million in Q2 2026, down 66% year-over-year, and do not include orders totaling approximately $7.0 million in revenue that were shipped on June 29, 2026 and arrived on July 1, 2026. These orders will be recognized as revenue in Q3 2026. PONVORY® net product sales were $7.9 million in Q2 2026, up 12% year-over-year. NEREUSTM net product sales were $1.0 million in Q2 2026. NEREUSTM launched commercially in the U.S. in Q2 2026 with the direct-to-consumer offering via the web portal nereus.us. Personal promotion is expected to commence later in 2026. Loss before income taxes was $62.4 million in Q2 2026 compared with $34.9 million in Q2 2025, reflecting continued investment in new product launches and pipeline advancement. Cash, cash equivalents and marketable securities (Cash) totaled $170.0 million as of June 30, 2026, representing a decrease to Cash of $32.3 million in Q2 2026. First Six Months of 2026 Total net product sales were $102.2 million in the first six months of 2026 as compared to $102.6 million in the first six months of 2025. Total net product sales does not include approximately $7.0 million of HETLIOZ® revenue for orders shipped on June 29, 2026 that arrived on July 1, 2026. Fanapt® net product sales were $65.5 million in the first six months of 2026, up 24% year-over-year. HETLIOZ® net product sales were $21.5 million in the first six months of 2026, down 42% year-over-year, and do not include orders totaling approximately $7.0 million in revenue that were shipped on June 29, 2026 and arrived on July 1, 2026. These orders will be recognized as revenue in Q3 2026. PONVORY® net product sales were $14.1 million in the first six months of 2026, up 11% year-over-year. NEREUSTM net product sales were $1.0 million in the first six months of 2026. NEREUSTM launched commercially in the U.S. in Q2 2026 with the direct-to-consumer offering via the web portal nereus.us. Personal promotion is expected to commence later in 2026. Loss before income taxes was $110.8 million in the first six months of 2026 compared with $72.3 million in the first six months of 2025, reflecting continued investment in new product launches and pipeline advancement. Cash, cash equivalents and marketable securities (Cash) totaled $170.0 million as of June 30, 2026, representing a decrease to Cash of $93.8 million compared to December 31, 2025. Key Commercial Highlights Fanapt® saw continued strong momentum in Q2 2026, with total prescriptions (TRx)1 up 31% and new-to-brand prescriptions (NBRx)1 up 32% versus Q2 2025. Since commercial expansion following the approval of bipolar disorder, Fanapt® has seen significant growth, with TRx1 up 62% and NBRx1 up 300% versus Q2 2024. BYSANTI™ received U.S. Food and Drug Administration (FDA) approval for the treatment of bipolar I disorder and schizophrenia in Q1 2026 and is expected to launch in the second half of 2026. BYSANTI™ is protected by data exclusivity through February 20, 2031 and multiple patents, the latest of which expires on May 31, 2044. In May 2026, the early commercial launch of NEREUS™ was initiated with a direct-to-consumer offering via the web portal nereus.us. Personal promotion is expected to commence later in 2026. Key Regulatory & Clinical Development Highlights Upcoming Clinical Milestones Vanda's ongoing late-stage clinical studies are progressing rapidly and are expected to generate topline results in 2026 or early 2027, including: The Thetis Phase III study of NEREUS™ for the prevention of vomiting in patients receiving GLP-1 receptor agonist therapies, with results expected in 2026. The Phase III study of VQW-765 in the treatment of adults with social anxiety disorder, with results expected in 2026. The Phase III study of HETLIOZ® in the treatment of delayed sleep phase disorder (DSPD), with results expected in 2026. The Phase III study of BYSANTI™ as a once-daily adjunctive treatment for major depressive disorder (MDD), with results expected in the first half of 2027. Other Updates The Biologics License Application (BLA) for Quimilza™ in Generalized Pustular Psoriasis (GPP) is under review by the FDA with a Prescription Drug User Fee Act (PDUFA) target action date of December 12, 2026. The results of the pivotal clinical study were published in the April 28, 2026 issue of the New England Journal of Medicine (NEJM) Evidence2. In May 2026, Vanda announced that Japan's Ministry of Health, Labour and Welfare (MHLW) granted orphan drug designation to Quimilza™ for the treatment of GPP. In July 2026, Vanda announced that the Committee for Orphan Medicinal Products at the European Medicines Agency (EMA) had adopted a positive opinion recommending orphan drug designation for Quimilza™ for the treatment of GPP. In July 2026, Vanda announced that the FDA had granted Rare Pediatric Disease Designation to VCA-894A, Vanda's investigational antisense oligonucleotide therapy for the treatment of Charcot-Marie-Tooth disease, axonal, type 2S (CMT2S), a rare, serious, and progressive inherited neurological disorder. Vanda continues to progress the FDA formal hearing regarding HETLIOZ® for the treatment of jet lag disorder. The proceeding, a rare administrative hearing process granted after the D.C. Circuit set aside the FDA's prior refusal to approve the application, is advancing according to schedule and is expected to culminate in a five-day hearing before the Administrative Law Judge in December 2026. GAAP Financial Results Net loss was $62.5 million (diluted loss per share of $1.04) in Q2 2026 compared with a net loss of $27.2 million (diluted loss per share of $0.46) in Q2 2025. Net loss was $111.1 million (diluted loss per share of $1.86) in the first six months of 2026 compared with a net loss of $56.7 million (diluted loss per share of $0.96) in the first six months of 2025. 2026 Financial Guidance Vanda is reiterating its 2026 total revenue guidance and expects to achieve the following financial objectives in 2026: Conference Call Vanda has scheduled a conference call for today, Wednesday, August 5, 2026, at 4:30 PM ET. During the call, Vanda's management will discuss the second quarter 2026 financial results and other corporate activities. Investors can call 1-888-596-4144 (domestic) or 1-646-968-2525 (international) and use passcode number 1843107. A replay of the call will be available on Wednesday, August 5, 2026, beginning at 8:30 PM ET and will be accessible until Wednesday, August 12, 2026 at 11:59 PM ET. The replay call-in number is 1-800-770-2030 for domestic callers and 1-609-800-9909 for international callers. The passcode number is 1843107. The conference call will be broadcast simultaneously on Vanda's website, . Investors should click on the Investors tab and are advised to go to the website at least 15 minutes early to register, download, and install any necessary software or presentations. The call will also be archived on Vanda's website for a period of 30 days. References IQVIA Prescription Data Smieszek, S. et al. Efficacy and Safety of Imsidolimab for Generalized Pustular Psoriasis. NEJM Evidence 5, (2026). About Vanda Pharmaceuticals Inc. Vanda is a leading global biopharmaceutical company focused on the development and commercialization of innovative therapies to address high unmet medical needs and improve the lives of patients. For more on Vanda Pharmaceuticals Inc., please visit and follow us on X @vandapharma. CAUTIONARY NOTE REGARDING FORWARD LOOKING STATEMENTS Various statements in this press release, including, but not limited to, the guidance provided under "2026 Financial Guidance" above and statements regarding Vanda's expectations with respect to its ability to fund its operations through at least the end of 2027; the expected timing of the commercial launch of BYSANTI™ for the treatment of bipolar I disorder and schizophrenia; the anticipated timing of the completion of the FDA's review of the Quimilza™ BLA for the treatment of GPP; Vanda's clinical development plans and expected timelines for NEREUS™ in the prevention of vomiting induced by GLP-1 therapies, VQW-765 in the treatment of adults with social anxiety disorder, HETLIOZ® in the treatment of DSPD, and BYSANTI™ for the treatment of MDD; Vanda's expectations with respect to its commercial expansion and ability to create value from its product pipeline; Vanda's expectations with respect to its operating expense run rate through 2027; the anticipated timing of the commencement of personal promotion of NEREUS™; Vanda's continued pursuit of FDA approval of HETLIOZ® for the treatment of jet lag disorder and Vanda's expectations with respect to the HETLIOZ® evidentiary hearing; and Vanda's expectations with respect to the strength of its business are "forward-looking statements" under the securities laws. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Forward-looking statements are based upon current expectations and assumptions that involve risks, changes in circumstances and uncertainties. Important factors that could cause actual results to differ materially from those reflected in Vanda's forward-looking statements include, among others, Vanda's ability to continue to grow its business; Vanda's ability to reduce its operating expenses, conserve cash and generate enough revenue to fund its operations through at least the end of 2027; Vanda's ability to successfully execute the commercial launch of BYSANTI™ for the treatments of bipolar I disorder and schizophrenia in the second half of 2026; the FDA's ability to complete its review of, and reach a decision with respect to, the BLA for Quimilza™ by December 12, 2026; Vanda's ability to continue to advance its late-stage clinical development programs and to obtain regulatory approval for, and successfully commercialize, the late-stage products in development; Vanda's ability to complete the Phase III studies for NEREUS™ in the prevention of vomiting induced by GLP-1 therapies, VQW-765 in the treatment of adults with social anxiety disorder, and HETLIOZ® in the treatment of DSPD and receive the respective study results by the end of 2026; Vanda's ability to complete the Phase III study for BYSANTI™ for the treatment of MDD and receive results in the first half of 2027; Vanda's ability to commence personal promotion of NEREUS™ for the prevention of vomiting induced by motion in 2026; and the outcome of the administrative hearing process for HETLIOZ® for the treatment of jet lag disorder. Therefore, no assurance can be given that the results or developments anticipated by Vanda will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, Vanda. Forward-looking statements in this press release should be evaluated together with the various risks and uncertainties that affect Vanda's business and market, particularly those identified in the "Cautionary Note Regarding Forward-Looking Statements", "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Vanda's most recent Annual Report on Form 10-K, as updated by Vanda's subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the U.S. Securities and Exchange Commission, which are available at . All written and verbal forward-looking statements attributable to Vanda or any person acting on its behalf are expressly qualified in their entirety by the cautionary statements contained or referred to herein. Vanda cautions investors not to rely too heavily on the forward-looking statements Vanda makes or that are made on its behalf. The information in this press release is provided only as of the date of this press release, and Vanda undertakes no obligation, and specifically declines any obligation, to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Corporate Contact: Kevin Moran Senior Vice President, Chief Financial Officer and Treasurer Vanda Pharmaceuticals Inc. 202-734-3400 [email protected] Jim Golden / Jack Kelleher / Dan Moore Collected Strategies [email protected] Follow us on X @vandapharma SOURCE Vanda Pharmaceuticals Inc. 21% more press release views with Request a Demo

阿尔茨海默病（AD）是最常见的痴呆形式，越来越多地与昼夜节律和睡眠-觉醒调节的紊乱相关联。本叙述性综述综合了近期关于昼夜节律功能障碍如何影响AD发病机制、生物标志物特征和治疗反应的文献。机制研究表明，核心生物钟基因与涉及氧化应激、神经炎症、胶质细胞反应性和蛋白质稳态的神经退行性级联反应之间存在重要相互作用。昼夜节律调控的分子通路（包括脑和肌肉ARNT样蛋白1（BMAL1）–去乙酰化酶1（SIRT1）、核因子κB（NF-κB）–NOD样受体家族含pyrin结构域蛋白3（NLRP3）以及周期昼夜调节因子2（PER2）–抗氧化信号通路）的紊乱可能损害神经元弹性并加重AD相关病理。新出现的证据还表明，AD相关生物标志物（包括褪黑素、皮质醇、食欲素、核心体温、血脑屏障通透性和胶质细胞标志物波动）存在独特的昼夜节律模式。这些节律性模式可能具有诊断和预后意义，并支持对生物标志物进行时间感知解读的需求。针对昼夜节律生物学的计时治疗策略，包括褪黑素受体激动剂、光疗、限时进食和昼夜节律对齐的药物递送系统，可能有助于改善AD的特定临床终点。本综述还讨论了计时表观遗传学作为一个新兴领域，其中时钟调控的表观遗传修饰可能影响神经退行性轨迹。未来方向包括新一代计时治疗靶点，如胶质细胞时钟、时钟门控炎症机制以及伴有昼夜节律调节的系统性合并症（包括糖尿病和高血压）。总体而言，现有证据支持昼夜节律紊乱与AD病理和治疗反应之间的密切关联，同时也指出了大规模临床试验中的重要空白。这种时间导向的视角可能支持开发个性化、生物标志物引导和节律知情的AD护理方法。通过连接时间生物学和神经退行性疾病，本综述强调了昼夜节律精准医学如何改进未来理解和管理AD的方法。1 引言（INTRODUCTION）阿尔茨海默病（AD）由Alois Alzheimer于1906年首次描述，以进行性记忆丧失、定向障碍和行为紊乱为特征，尸检发现淀粉样斑块和神经原纤维缠结。尽管研究数十年，但β-淀粉样蛋白（Aβ）和tau蛋白积累的确切机制仍不清楚。当前观点将AD视为多因素疾病，涉及遗传易感性、环境暴露和全身健康因素。全球AD负担持续上升，2016年痴呆患者达4380万，为第五大死因，造成约240万死亡。超过640万伤残调整生命年（DALYs）归因于可改变风险因素。预计到2050年，全球AD及其他痴呆患者将达1.53亿。昼夜节律生物学已成为理解AD发病可改变因素的重要框架。昼夜节律紊乱不仅被认为是神经退行性变的结果，也是早期特征，可能促进AD发病。视交叉上核（SCN）功能障碍、睡眠-觉醒周期改变以及应激和免疫反应的昼夜节律调节受损可能导致神经元损伤和疾病进展。临床上，日落综合征（傍晚激越、混乱和行为失调）体现了昼夜节律紊乱与AD症状的相关性。时间生物学基础研究（从时钟基因发现到耦合振荡器系统模型）为“昼夜节律医学”奠定了基础，即将时间变量纳入肿瘤学、神经病学、代谢疾病和心血管医学的治疗中。本综述总结核心昼夜节律机制及其与神经退行性变的联系，考察昼夜节律知情的生物标志物和治疗策略，并概述将计时疗法整合到AD研究和护理中的未来方向。2 方法学（METHODOLOGY）本研究为叙述性综述，以PubMed为主要数据库进行结构化文献检索。对于新兴机制通路或生物标志物特定小节，进行手动检索和参考文献筛选。检索策略结合了医学主题词（MeSH）和自由文本关键词，涵盖AD、昼夜节律、时钟基因（BMAL1、CLOCK、PER、CRY）、睡眠-觉醒调节、生物标志物（褪黑素、皮质醇、体温、视网膜变化、血脑屏障[BBB]）、胶质细胞（星形胶质细胞和小胶质细胞）、肠-脑轴、计时表观遗传学和计时疗法。使用布尔运算符（AND、OR）优化检索。纳入2000年1月至2025年5月发表的文章，重点关注2020-2025年文献。两名研究者独立筛选，通过讨论或第三方裁决解决分歧。纳入同行评审的原创研究、系统综述和临床试验，排除非英文出版物、会议摘要、病例报告和社论，以及与昼夜节律调节或AD无关的研究。最终纳入109项研究。由于是叙述性综述，未使用正式系统流程图，如PRISMA流程图。研究质量和相关性根据方法清晰度、主题相关性和与更广泛证据的一致性进行定性评估，并按主题章节组织综合。3 昼夜节律与AD（CIRCADIAN RHYTHMS AND AD）3.1 昼夜节律的基本原理昼夜节律是内在的24小时周期，调节生理过程，由中央时钟（SCN）和外周时钟协调控制。授时因子（Zeitgebers）是同步中央时钟的外部线索，光是最强授时因子，此外还包括食物摄入、温度、体力活动和社交互动。分子层面，昼夜节律时钟基因调控睡眠-觉醒周期、代谢和激素分泌。昼夜节律失调（内源性时钟与外部环境不匹配）因现代生活方式（如晚间人工光照、屏幕使用增加、活动减少、不规律工作）而日益普遍，被视为AD早期且可改变的特征，可能促进睡眠碎片化、日落综合征，并与Aβ和tau积累相关。光作为最强授时因子，荟萃分析表明光疗可改善老年痴呆患者的睡眠质量，减少夜间觉醒。3.2 昼夜节律紊乱作为AD的可改变风险因素昼夜节律紊乱不仅是AD的结果，也可能是可改变的风险因素。在认知症状出现前常观察到昼夜节律变化，提示SCN早期功能障碍以及激素、代谢和睡眠-觉醒调节改变。这种紊乱可能形成双向反馈环：神经退行性变加重昼夜节律失调，而昼夜节律失调进一步促进神经退行性过程。核心时钟基因如BMAL1和CLOCK调节昼夜节律，并参与氧化应激、炎症和记忆，是潜在治疗靶点。microRNA失调（如miR-16下调及其与CLOCK蛋白的相互作用）进一步支持昼夜节律失调作为治疗切入点。hypocretin/orexin系统可能参与，升高的orexin水平损害类淋巴清除，将长期觉醒状态与AD病理联系起来。环境昼夜节律紊乱（如夜班工作）与氧化应激和DNA损伤相关，这些过程与神经退行性变相关联。3.3 昼夜节律门控与AD中的睡眠障碍昼夜节律门控通过决定生物学事件（如激素分泌、免疫反应、代谢、基因表达）在24小时周期中最活跃的时间来调节生理过程。该机制紊乱可损害免疫稳态、代谢清除和睡眠质量，这些均与AD发病相关。现代生活方式（如人工夜间光照[ALAN]、轮班工作、不规律进食或睡眠时间）加剧昼夜节律失调，导致睡眠障碍、内皮功能障碍、止血改变、代谢变化和炎症加剧，进而促进脑血管病理和认知衰退。昼夜节律时钟基因失调（尤其在肾素-血管紧张素-醛固酮系统中）在心血管和神经退行性疾病中均有观察到，提示共享机制通路。限时进食（TRE）作为一种行为干预，可支持昼夜节律对齐。研究表明TRE与较低的Aβ42沉积、减少全身性炎症以及更强的中枢和外周昼夜节律完整性相关，对睡眠调节和认知表现有潜在益处。3.4 昼夜节律对分子降解途径的影响蛋白质稳态（proteostasis）涉及蛋白质合成、折叠和降解的平衡，受昼夜节律严格调控。在AD中，昼夜节律定时紊乱可能损害蛋白质稳态机制。纠正昼夜节律功能障碍有助于恢复关键神经生物学过程，包括错误折叠蛋白的降解和清除。昼夜节律对齐的干预措施（如结构化休息、进食计划和靶向核心时钟通路的小分子）可调节细胞应激反应，增强分子修复。蛋白质降解系统（包括自噬和泛素-蛋白酶体系统）受昼夜节律控制，在AD中受损。TRE可通过改善昼夜节律调节的类淋巴清除和炎症状态降低脑Aβ42水平，提示恢复昼夜节律对齐可能重新平衡AD中破坏的蛋白质稳态网络。4 连接昼夜节律与神经退行性变的机制（MECHANISMS LINKING CIRCADIAN RHYTHMS AND NEURODEGENERATION）4.1 连接昼夜节律紊乱与神经退行性变的分子机制昼夜节律紊乱在AD患者中一致观察到，但连接时钟基因功能障碍与氧化应激、蛋白质稳态失败和神经炎症的详细分子证据主要来自动物模型和细胞系统。人类研究支持昼夜节律紊乱、睡眠碎片化、淀粉样蛋白负荷和认知衰退之间的关联，但直接因果证据有限。BMAL1和CLOCK是核心昼夜节律基因，参与氧化应激、炎症和神经元稳态，神经退行性变与时钟基因功能障碍存在双向关系。这些基因还调节基因组维持途径，包括DNA复制、检查点信号和DNA修复，其节律紊乱可能降低修复保真度，促进基因组不稳定性。昼夜节律时钟与细胞周期之间存在机械耦合，时钟控制基因同步有丝分裂定时和DNA修复，协调丧失可能损害神经发生，导致年龄相关性神经元衰退。昼夜节律时钟基因还门控认知过程，如记忆和突触可塑性。在AD中，中央SCN与区域脑时钟之间的去同步化被认为破坏可塑性节律，促进认知恶化。这种前馈循环支持通过计时疗法重新同步脑时钟的评估。帕金森病中也描述了类似早期昼夜节律改变，支持个性化节律干预在神经退行性疾病中的潜在转化价值。4.2 胶质细胞及其在神经退行性变昼夜节律调节中的作用星形胶质细胞现被认为是昼夜节律的重要调节者，调节神经元信号、神经递质循环和睡眠-觉醒调节。在AD中，星形胶质细胞时钟的紊乱与昼夜节律和神经退行性变化有关，可能导致睡眠碎片化、神经炎症和认知衰退。星形胶质细胞表现出内在Ca2+节律性，促进SCN神经元放电协调并稳定下游睡眠-觉醒节律。Ca2+振荡干扰可减弱时钟基因节律性并削弱SCN输出强度，解释了星形胶质细胞信号异常如何导致AD中昼夜节律衰退。Tau病理（AD标志）可损害SCN的神经元和胶质细胞成分，Tau在SCN内积累可改变核心时钟基因表达并损害星形胶质细胞支持，导致昼夜节律失调并与更差的认知结局相关。这些发现强调了SCN内胶质-神经元回路的双向脆弱性，支持基于星形胶质细胞的昼夜节律干预在AD中的进一步研究。4.3 双向反馈环模型（昼夜节律–SCN–AD）昼夜节律紊乱与AD之间可能存在双向反馈环。早期SCN功能障碍、睡眠-觉醒碎片化、类淋巴清除减少以及Aβ/tau积累与神经炎症和代谢通路相互作用。昼夜节律调节紊乱促进炎症、氧化应激和错误折叠蛋白积累，而AD病理进一步损害昼夜节律输出，形成自我维持的病理循环。睡眠障碍既是AD早期症状，也促进疾病进展：慢波睡眠受损减少Aβ的类淋巴清除，进行性神经退行性变碎片化昼夜节律调节的睡眠结构，促进Aβ和tau沉积。星形胶质细胞介导的神经炎症和mTOR通路失调进一步连接昼夜节律功能障碍与AD分子框架。昼夜节律失调还涉及肠道微生物群：失调破坏微生物群节律性，通过微生物群-肠-脑轴损害神经免疫通讯，促进全身性炎症和认知衰退。SCN与海马昼夜节律网络之间的通讯对于维持突触可塑性和记忆功能的昼夜模式至关重要，协调减弱时认知表现可能全天波动，导致临床行为时间碎片化。下丘脑失调（尤其在代谢和内分泌通路中）可能促进神经退行性级联反应。阻塞性睡眠呼吸暂停（OSA）和非杓型高血压是重要的昼夜节律相关合并症，可损害神经血管健康，导致BBB损伤、间歇性缺氧和增强神经炎症。4.4 AD分子通路中的昼夜节律和睡眠障碍昼夜节律紊乱可干扰代谢、突触可塑性和记忆巩固等生理过程，可能促进神经退行性变而非仅作为继发后果。蛋白质稳态受昼夜节律控制，年龄相关的蛋白酶体功能下降可能损害时钟基因调节和错误折叠蛋白清除，加重AD病理。在AD中，SCN结构完整但下游昼夜节律信号受损，导致广泛节律紊乱，可能延伸至外周振荡器和感觉回路。SCN和非SCN脑时钟在AD中均易受损，昼夜节律失调促进淀粉样蛋白积累并损害神经生理稳态。除认知症状外，昼夜节律定时还影响运动功能，下午步态和平衡改善提示时间因素可能增强AD康复效果。睡眠剥夺通过类淋巴功能障碍、tau病理、胶质细胞激活和orexin失调加剧AD，这些机制与昼夜节律控制密切相关。代谢疾病如2型糖尿病可能与AD通过共享昼夜节律机制（涉及胰岛素抵抗、氧化应激和时钟基因紊乱）相关联，支持节律对齐策略如褪黑素、光疗和限时进食的进一步评估。5 昼夜节律紊乱及其对AD的影响（CIRCADIAN DISRUPTION AND ITS IMPACT ON AD）5.1 昼夜节律失同步与AD发病昼夜节律失同步反映了中枢和外周系统协调生物定时的崩溃。在AD中，失同步影响情绪调节、睡眠、激素轴和蛋白质稳态等多个领域。时钟基因表达失调和硝化氧化应激通路可能通过氧化还原平衡受损和突触不稳定性促进神经退行性变。昼夜节律失调增加神经系统疾病易感性，而持续病理逐渐破坏昼夜节律控制，形成前馈循环。时钟基因通过细胞类型特异性机制调节神经元兴奋性、突触可塑性和神经递质释放，为AD中焦虑和日落综合征等神经精神症状提供基础，部分由应激相关昼夜节律失调和边缘系统-SCN耦合改变介导。睡眠是昼夜节律系统的行为输出，也是认知衰退的潜在前驱标志：近45%的认知障碍患者存在睡眠障碍（失眠、OSA、异常睡眠时长），这些障碍在临床表现为前即出现，与Aβ负荷增加和快速眼动（REM）睡眠异常相关。orexin系统影响睡眠-认知轴，双重orexin受体拮抗剂（DORAs）改善睡眠质量，可能调节淀粉样蛋白和tau病理。皮质醇节律性在神经炎症、海马萎缩和tau过度磷酸化中发挥作用，扁平或倒置的皮质醇模式可能进一步促进AD相关脑改变。蛋白质稳态失败破坏睡眠调节，通过自噬和类淋巴途径减少神经毒性蛋白清除，恶化神经元回路功能障碍。昼夜节律时钟调节氧化应激反应、线粒体稳态和蛋白质降解途径，这些核心过程失败标志AD病理早期阶段。昼夜节律控制NLRP3炎症小体调节每日炎症波动，时钟紊乱可能通过失调的IL-1β和IL-18信号放大无菌性神经炎症。5.2 神经退行性变中的激素失调激素失调与昼夜节律紊乱密切相关，在AD发病中起重要作用。关键激素（皮质醇、褪黑素、胰岛素、甲状腺激素）的节律性分泌在中央昼夜节律控制破坏时改变，产生全身性和神经炎症后果。昼夜节律失调通过氧化应激和炎症加速血管衰老，间接损害涉及皮质醇和褪黑素的神经内分泌反馈环。甲状腺激素紊乱与认知衰退、脑代谢改变和AD患者昼夜节律异常相关，表明复杂的神经内分泌-昼夜节律相互作用。激素节律受SCN中枢调控，光疗和褪黑素补充等昼夜节律对齐干预可能有助于恢复内分泌稳定性，防止认知恶化。5.3 AD昼夜节律相关分子生物标志物与计时疗法昼夜节律生物学在塑造AD早期检测、风险分层和治疗监测的生物标志物谱中起重要作用。许多AD相关生物标志物呈现昼夜变化，影响诊断准确性和生物学解释。血脑屏障（BBB）表现出昼夜节律变化，其节律性调节影响药物递送、睡眠行为和神经退行性易感性，BBB可作为动态、时钟控制的生物标志物候选。系统昼夜节律标志物如体温节律（CRBT）可作为昼夜节律阶段和免疫稳态的实时指标，CRBT紊乱可能指示免疫失调和昼夜节律失调，提供无创计时治疗研究指导。小胶质细胞（脑内驻留免疫细胞）受昼夜节律时钟基因调节，影响其吞噬活性和炎症输出，昼夜节律失调损害淀粉样蛋白清除并增强神经炎症，小胶质细胞节律性可作为免疫计时治疗的靶点。小胶质细胞表现出昼夜代谢周期（糖酵解活性、线粒体功能和NAD+依赖氧化还原波动），昼夜节律失调破坏这些代谢周期，增加小胶质细胞反应性，降低淀粉样蛋白清除能力，加强早期神经炎症信号。褪黑素是昼夜节律相关生物标志物中研究最广泛的之一，调节自噬、氧化应激、线粒体功能和时钟基因表达，作为生物标志物和治疗剂均有价值。褪黑素促进自噬清除毒性蛋白，支持海马神经发生和昼夜节律重新对齐。褪黑素节律丧失（特别是脑脊液和唾液中水平降低）与海马早期tau积累相关，提示昼夜节律紊乱可能先于认知衰退。人工光暴露抑制褪黑素合成，导致“黑暗缺乏”，加剧昼夜节律失衡。尽管临床试验结果不一，褪黑素在早期AD中可能提供适度的认知和行为获益，尤其在昼夜节律对齐给药时。昼夜节律降解可预测AD风险：活动减少和日常活动节律碎片化增加AD发病率和疾病进展速度。客观评估的昼夜节律休息-活动模式可作为早期风险指标和预防研究终点。并非所有节律性生物标志物在AD中均受损：尽管基础皮质醇水平升高，但皮质醇昼夜节律保持完整，提示皮质醇分泌过多可作为独立于核心昼夜节律紊乱的时间敏感生物标志物。5.4 生物标志物知情的AD计时治疗靶点昼夜节律调节生理稳态，作为AD治疗创新靶点。褪黑素是最广泛研究的计时治疗剂，调节睡眠-觉醒周期、氧化应激、神经炎症和毒性蛋白聚集。AD中褪黑素水平下降，补充显示症状和可能的疾病修饰潜力，但临床结果异质。睡眠障碍在AD前驱期常见，通过昼夜节律失调和神经递质失衡促进Aβ和tau病理，针对睡眠结构和orexin系统的干预可能提供早期神经保护。内源性大麻素系统是潜在计时生物学调节者，大麻素受体与核心时钟基因相互作用调节神经传递和免疫反应，其功能障碍通过tau错误加工和小胶质细胞激活加重神经退行性变。昼夜节律失调增加神经退行性变易感性并影响药物疗效，将昼夜节律阶段纳入治疗方案可增强治疗效果并减少不良反应。癌症计时疗法见解提示靶向转录-翻译反馈环（TTFL）调节者（如BMAL1、CLOCK、CRY）可能与AD相关，这些因素与蛋白质清除和代谢稳态密切相关。蛋白质组学分析显示昼夜节律紊乱失调自噬、炎症和突触信号相关蛋白，支持精准计时治疗发展。临床证据包括lemborexant（DORA）的2期试验，改善AD伴不规则睡眠-觉醒节律障碍患者的昼夜节律对齐和睡眠效率，未恶化认知。Tg-SwDI小鼠模型（复制实质和血管淀粉样病理及昼夜节律紊乱）提供评估时间敏感干预的转化平台。昼夜节律表型分型和时钟靶向药物（如AhR激活破坏BMAL1和CLOCK表达并损害类淋巴清除）将肠-脑轴功能障碍与AD病理联系起来，AhR作为潜在昼夜节律靶点。昼夜节律调节者与蛋白质稳态通路之间的分子串扰（如PARP1和E3连接酶）可能增强tau和α-突触核蛋白聚集，加速神经退行性变。5.5 代谢和系统性昼夜节律生物标志物及计时治疗意义与昼夜节律对齐的治疗策略可能改善AD等神经退行性疾病的选定结局。时间药理学显示昼夜节律定时影响药物药代动力学和药效学（吸收、疗效、毒性）。昼夜节律对齐的药物递送（计时疗法）可提高AD治疗精度。褪黑素具有抗氧化、抗炎和自噬调节作用，促进线粒体自噬并限制Aβ和tau等错误折叠蛋白的毒性积累，作为计时治疗剂恢复昼夜节律对齐同时保护神经。Adropin（一种具有昼夜节律性的肽）是连接代谢、内皮功能和自主神经张力的潜在介质，失调的adropin可能通过“代谢-自主神经系统-昼夜节律”轴促进血管功能障碍和认知障碍。个性化计时疗法由褪黑素、adropin等昼夜节律生物标志物指导，整合代谢健康与生物定时。昼夜节律调节在大脑和全身代谢稳态维持中起主要作用，分子昼夜节律时钟协调关键代谢功能（脂质利用、葡萄糖代谢、线粒体活性、胰岛素敏感性）。节律紊乱（由于衰老、不规律生活方式或环境失调）可能损害代谢效率，促进神经退行性进展。基于血浆代谢组学的昼夜节律阶段预测技术可个性化干预治疗定时。脑内时钟基因（CLOCK、BMAL1、PER、CRY）调节脂质代谢，其去同步化引发氧化应激、神经炎症和突触不稳定性，与Aβ和tau病理相关。睡眠障碍（与昼夜节律失调密切相关）可放大这些代谢失衡并恶化认知症状。结合非药物方法（光疗、活动安排）和计时治疗剂（褪黑素、DORAs）可能支持昼夜节律控制。昼夜节律与肠道微生物群完整性破坏构成AD中汇聚的病理生理机制，形成动态的肠道-时钟-脑轴。肠道失调增加肠通透性，允许促炎和神经毒性代谢物（如TMAO、SCFAs、钙卫蛋白）全身移位，参与Aβ和tau病理。BMAL1在维持肠道免疫节律性和微生物平衡中起核心作用，其功能障碍破坏黏膜免疫和氧化稳态，加重神经炎症。肠道来源代谢物改变外周和中央时钟基因表达，形成昼夜节律和微生物失调的前馈环。睡眠-昼夜节律紊乱在早期AD中常见，进一步减弱微生物节律性，减少SCFA产生菌，促进全身性炎症。昼夜节律失调的肠-脑脂质代谢损害膜动力学和钙稳态，引发内质网应激，放大神经退行性级联反应。5.6 AD的视网膜生物标志物视网膜是神经系统的延伸，可提供AD病理的无创窗口。AD特征（Aβ斑块、过度磷酸化tau、神经元丢失、胶质增生）在视网膜中可检测到，且可能先于认知衰退。视网膜血管异常（周细胞丢失、PDGFR-β表达降低）与脑淀粉样血管病相关，加强视网膜-脑病理联系。视网膜通过含黑视蛋白的视网膜神经节细胞对光授时系统做出贡献，视网膜变性可能参与AD中观察到的昼夜节律紊乱。先进成像技术（OCT、高光谱成像、淀粉样蛋白靶向视网膜扫描）可提供时间生物学和诊断见解，将视网膜定位为昼夜节律相关神经退行性变的机制贡献者和生物标志物平台。5.7 计时表观遗传学：AD的新前沿计时表观遗传学在AD病理生理中可能起重要作用。护理环境中的光照不足通过破坏神经内分泌和昼夜节律网络加剧日落综合征和行为症状，光作为表观遗传学影响节律的调节者。在AD中，新皮质昼夜和季节性基因表达模式减弱，伴随DNA甲基化和组蛋白修饰减弱，这是衰老大脑中昼夜节律失同步的标志。SIRT1作为昼夜节律和神经保护通路的核心表观遗传整合者，通过去乙酰化BMAL1和PER2维持节律性转录周期，同时调节神经炎症、氧化和淀粉样蛋白生成通路，表明表观遗传时钟调节在AD发病中的直接作用。AD皮质组织中昼夜节律甲基化节律丧失和染色质周期受损进一步支持SIRT1-DNMT-HDAC轴作为潜在治疗干预节点。恢复表观遗传学调控的昼夜节律可能成为AD预防和计时治疗的潜在策略。6 治疗方法与计时疗法（THERAPEUTIC APPROACHES AND CHRONOTHERAPY）6.1 计时疗法作为AD的潜在治疗方法计时疗法是优化AD特定治疗结局的策略，涉及节律恢复（如褪黑素或光疗）和基于个体时间类型的时间给药。计时定制药物递送系统通过同步药物释放与生物节律增强疗效并减少不良反应。时间依赖性药理学优化受昼夜节律调节的吸收、代谢和排泄（由时钟控制基因介导）影响药物安全性和效力。现有临床证据异质：光疗和褪黑素的人类试验显示对睡眠和行为症状的适度但不一致获益，其修饰潜在疾病过程的能力不确定。时间类型知情的药物定时和生物标志物引导的治疗策略正在出现，但需更大规模验证。若干机制靶点（时钟基因调节、节律同步神经调控、分子时钟-代谢界面）仍处于临床前或早期研究阶段。生物标志物引导的计时疗法（根据褪黑素、皮质醇和时钟基因表达个性化）可能改善精神病护理结局。昼夜节律通路被识别为AD药物研发管线中新兴疾病修饰靶点，呼吁整合时间效应的生物标志物关联试验。节律同步神经调控作为未来计时疗法扩展，提出实时脑刺激与患者特异性昼夜节律模式对齐。AD试验中昼夜节律对齐技术需标准化昼夜节律阶段测量，并与当前疾病修饰疗法（如lecanemab）一起评估，同时需明确定义的时间给药方案。6.2 AD的计时治疗睡眠管理框架睡眠障碍是AD发病和进展的可改变因素。失眠、OSA和昼夜节律障碍在AD前驱期和晚期均常见，通过损害Aβ和tau蛋白的类淋巴清除促进神经退行性变。应避免过度依赖镇静药物（因跌倒和认知恶化风险），提倡通过非药物和计时治疗干预早期并持续管理睡眠障碍。睡眠疗法可作为早期失调的预防措施和症状阶段的治疗策略，睡眠-觉醒调节在神经保护中的核心作用支持将睡眠干预整合到综合AD管理框架中。6.3 昼夜节律卫生与AD环境风险因素昼夜节律卫生在减轻AD风险和进展中起重要作用，包括结构化行为模式、环境对齐和代谢调节。TRE（基于生活方式的干预，将食物摄入与生物节律对齐）对神经可塑性、睡眠和认知功能显示潜在益处。环境干扰物如人工光暴露和光污染可慢性损害昼夜节律信号，触发神经炎症、氧化应激和Aβ/tau失调，促进神经退行性变。这些环境和生活方式影响部分通过核心昼夜节律基因发挥作用，这些基因调节自噬、线粒体功能和神经营养信号通路（涉及SIRT1、mTOR和FoxO）。临床上，AD中睡眠障碍常见，且被确认为疾病轨迹的主动调节者，强调早期筛查和非镇静、昼夜节律对齐干预的重要性。SIRT1作为昼夜节律、代谢和神经炎症之间的桥梁，对环境输入（运动、饮食、压力）有反应，支持基于精准生活方式的计时治疗策略在AD护理中的进一步评估。7 AD计时疗法的未来方向（FUTURE DIRECTIONS IN CHRONOTHERAPY FOR AD）7.1 新一代计时治疗靶点昼夜节律科学兴趣增加，AD治疗格局向节律知情的精准干预转变。昼夜节律影响广泛生理过程和疾病通路，其对药物代谢和疗效的影响日益被认识，部分由肝脏酶（如CYP450s）的振荡活性和时钟调节核受体介导。这些见解支持时间药理学机制基础，可能实现更安全、有效和个体时间定制的药物方案，但缺乏AD特异性计时治疗试验。褪黑素是最广泛研究的昼夜节律激素，其受体MT1和MT2是潜在分子靶点。靶向这些受体的治疗剂（缓释褪黑素、雷美替胺、他司美琼、阿戈美拉汀）可能恢复昼夜节律完整性并改善睡眠和记忆结局。阿戈美拉汀通过额外拮抗5-HT2C受体增强多巴胺能和去甲肾上腺素能张力，可能提供认知或情绪相关获益，但疾病修饰证据仍初步。分子伴侣和