Valiltramiprosate

Phase 3 and Phase 2 Studies in APOE4/4 Alzheimer’s Patients Show Favorable Safety, Low Risk for Brain Bleed and Edema (ARIA), and Neurovascular Protection Long-Term Phase 3 and Phase 2 Extension Data Support Precision Medicine Approach in High-Risk APOE4/4 Patients with Mild Cognitive Impairment (MCI) Nine Posters Highlight New DTI, Volumetric MRI, and Plasma p-tau217 Findings Supporting Sustained Clinical and Brain Atrophy Benefits in MCI Patients Valiltramiprosate Could Become First Oral Therapy to Slow Alzheimer’s Pathology FRAMINGHAM, Mass.--(BUSINESS WIRE)-- #ALZ801 -- Alzheon, Inc. , a clinical-stage biopharmaceutical company developing investigational therapies and diagnostic assays for Alzheimer’s disease (AD) and other neurodegenerative disorders, today announced that it will present nine posters on its lead investigational therapy, valiltramiprosate/ALZ-801 , at the 2026 Alzheimer’s Association International Conference (AAIC) in London, United Kingdom. The presentations will feature expanded analyses from the Phase 3 APOLLOE4 and Phase 2 biomarker trials and their long-term extensions, including new evidence of neurovascular protection; diffusion tensor imaging (DTI) and volumetric MRI (vMRI) correlations with clinical outcomes; sustained long-term efficacy and safety; and a quantitative systems pharmacology (QSP) analysis evaluating valiltramiprosate as a potential oral maintenance therapy for AD following plaque clearance with anti-amyloid antibody treatments. “Our AAIC presentations reflect more than a decade of disciplined execution in addressing one of the most urgent global unmet needs: Alzheimer’s disease in APOE4/4 patients, who carry the greatest genetic risk and are most vulnerable to complications from anti-amyloid antibodies,” said Martin Tolar, MD, PhD, Founder, President and CEO of Alzheon. “Across nine presentations covering Phase 3 efficacy and safety, imaging and plasma biomarkers, long-term safety, and a new analysis of valiltramiprosate as a potential oral maintenance therapy after anti-amyloid antibody treatment, we are positioning valiltramiprosate as a foundational oral therapy and strengthening Alzheon’s precision medicine platform. If approved, we are committed to making valiltramiprosate available to the patients who need it most, and to potentially extending its benefits to broader APOE4 populations in the years ahead.” Valiltramiprosate/ALZ-801 is an investigational oral agent in Phase 3 development as a potential first-in-class, disease-modifying treatment for Alzheimer’s disease. It acts upstream of anti-amyloid antibodies by inhibiting the formation of neurotoxic soluble amyloid oligomers. The Phase 3 program targets patients with MCI who are homozygous for the apolipoprotein ε4 allele (APOE4/4), a group that represents approximately 15% of all Alzheimer’s patients. Because APOE4/4 AD patients have a high prevalence of cerebral amyloid angiopathy (CAA), they are particularly vulnerable to brain edema and microhemorrhage complications associated with anti-amyloid antibody therapies, known as amyloid-related imaging abnormalities (ARIA). The AAIC presentations will report neurovascular and ARIA outcomes from the placebo-controlled APOLLOE4 trial. These findings in APOE4/4 patients may also have implications for treating CAA patients and adults with Down syndrome, who similarly have a high prevalence of underlying CAA. The presentations will also include diffusion tensor imaging and volumetric MRI analyses of hippocampal microstructure; plasma p-tau217 findings; biomarker correlations with imaging and clinical endpoints; sustained efficacy and safety data from long-term extension studies of up to four years; and a quantitative systems pharmacology (QSP) evaluation of valiltramiprosate as a potential oral maintenance therapy following donanemab or lecanemab treatment. “Although the Phase 3 trial did not meet its primary endpoint, we believe the new Phase 3 and long-term extension analyses being presented at AAIC reinforce valiltramiprosate’s differentiated pro one of the few oral anti-amyloid agents with the potential to slow disease progression while preserving vascular integrity in APOE4/4 Alzheimer’s patients,” said Susan Abushakra, MD, Chief Medical Officer of Alzheon. “The expanded Phase 3 analyses showed consistent neurovascular protection, including lower ARIA rates in the overall population versus placebo, together with clinically meaningful benefits on cognition and brain volume in the pre-specified MCI subgroup from the Phase 3 and Phase 2 long-term extension studies. New diffusion tensor imaging analyses further demonstrated preservation of hippocampal microstructure and correlations with clinical and brain volume outcomes. We believe these structural effects, together with a significant reduction in plasma p-tau217 in the overall population, support the disease-modifying potential of valiltramiprosate. Importantly, long-term extension findings in APOE4/4 and APOE3/4 carriers continue to show a favorable safety profile, with no symptomatic ARIA-E or ARIA-H observed through up to four years of treatment.” Details of Presentations at AAIC 2026 Conference Sunday, July 12, 2026 Time: 7:30AM – 4:15PM GMT Poster: Significant Positive Correlations Between Microstructure and Efficacy/Brain Atrophy of Oral Valiltramiprosate in APOE4/4 MCI Subjects Presenter: Earvin Liang, PhD, Vice President of Clinical Development, Alzheon, Inc. Poster: Valiltramiprosate on Plasma p-Tau217, p-Tau217/Ab42, vMRI and Clinical Correlations in Phase 3 APOE4/4 Early AD Subjects Presenter: John A. Hey, PhD, Chief Scientific Officer, Alzheon, Inc. Monday, July 13, 2026 Time: 7:30AM – 4:15PM GMT Poster: Valiltramiprosate Reduced ARIA Rates in APOE4/4 with Early AD: Results of Phase 3 APOLLOE4 Trial and CAA Implications Presenter: Earvin Liang, PhD, Vice President of Clinical Development, Alzheon, Inc. Poster: Valiltramiprosate Improves Hippocampal Microstructure and Clinical Outcomes in APOE4/4: Phase 3 DTI and vMRI in Early AD Presenter: Jeremy Yu, MD, PhD, Senior Research Fellow, Alzheon, Inc. Poster: Oral Valiltramiprosate Shows Sustained CDR-SB Benefit Over 2.5 Years in APOE4/4 MCI Subjects: APOLLOE4 Phase 3 Long-term Extension Results Presenter: Susan Abushakra, MD, Chief Medical Officer, Alzheon, Inc. Tuesday, July 14, 2026 Time: 7:30AM – 4:15PM GMT Poster: Safety of Oral ALZ-801 in APOE4/4 and APOE3/4 Subjects with Early AD in Long-term Extension Studies up to 4 Years Presenter: Aidan Power, MB, BCh, MRCPsych, Chief Development Officer, Alzheon, Inc. Poster: Valiltramiprosate in Biomarker-positive APOE4/4 MCI Subjects Shows Clinical Stability and Slows Atrophy Over 4-years Presenter: Patrick Kesslak, PhD, Senior Research Fellow, Alzheon, Inc. Poster: Valiltramiprosate Effects on Cerebellar Volume in APOE4/4 Early Alzheimer’s Disease Subjects from Phase 3 APOLLOE4 Study Presenter: Susan Abushakra, MD, Chief Medical Officer, Alzheon, Inc. Wednesday, July 15, 2026 Time: 7:30AM – 4:15PM GMT Poster: Oral Valiltramiprosate Maintenance Therapy After Donanemab and Lecanemab Treatment: QSP Analysis of Amyloid Aggregation by APOE Genotype Presenter: Jean F. Schaefer, Vice President of CMC & Project Management, Alzheon, Inc. About ALZ-801 Valiltramiprosate/ALZ-801 is an investigational oral agent currently in Phase 3 development as a potential first-in-class, disease-modifying treatment for Alzheimer’s disease. 3-7,9,12 Valiltramiprosate is designed to inhibit the formation of neurotoxic soluble beta amyloid oligomers that contribute to cognitive decline in individuals with AD. 4-8,10,15 Preclinical mechanism-of-action studies have demonstrated that ALZ-801 can completely block the formation of these neurotoxic oligomers at the dosage used in Phase 3 clinical trials. 3,9,12,14 Valiltramiprosate employs an enveloping molecular mechanism of action intended to prevent the aggregation of soluble amyloid oligomers in the human brain, 14 which are associated with the onset and progression of cognitive impairment in AD patients. 3,4,7,9,10 In recognition of its therapeutic promise, valiltramiprosate received Fast Track designation from the U.S. Food and Drug Administration in 2017 for the treatment of Alzheimer’s disease. Clinical trial data suggest that valiltramiprosate exhibits strong clinical efficacy at the MCI stage, and a favorable safety profile, with no observed increase in the risk of brain vasogenic edema. 1-10,13,15 The initial Phase 3 program for valiltramiprosate targets Early AD patients who are homozygous for the apolipoprotein ε4 allele (APOE4/4), with plans to expand future research to include AD treatment and prevention in individuals carrying one copy of the APOE4 gene. 3–10 Valiltramiprosate APOLLOE4 Phase 3 Trial An Efficacy and Safety Study of Valiltramiprosate in APOE4/4 Early Alzheimer's Disease Subjects ( NCT04770220 ): This trial was designed to evaluate the efficacy, safety, biomarker and imaging effects of 265 mg twice daily oral dose of valiltramiprosate in Early AD subjects with two copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), who constitute approximately 15% of Alzheimer's patients. This double-blind, randomized trial compared oral valiltramiprosate to placebo treatment over 78 weeks. The APOLLOE4 trial was supported by a grant from the National Institute on Aging to Alzheon, with Susan Abushakra as the principal investigator. Valiltramiprosate APOLLOE4 Long Term Extension Trial (Phase 3 LTE) A long-term extension of the trial, APOLLOE4-LTE, evaluated valiltramiprosate in subjects who complete the core APOLLOE4 study for an additional 104 weeks of treatment for a total of 182 weeks or 3.5 years over the core and LTE study. This LTE study ended in January 2026 ( NCT06304883 ). Valiltramiprosate Phase 2 Biomarker Trial Biomarker Effects of Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease ( NCT04693520 ): This trial was designed to evaluate the effects of 265 mg twice daily oral dose of valiltramiprosate on biomarkers of AD pathology in subjects with Early AD, who have either the APOE4/4 or APOE3/4 genotype and constitute 65-70% of Alzheimer's patients. The primary outcome was the change from baseline in plasma p-tau 181 . The trial also included evaluation of clinical efficacy, safety, tolerability, and pharmacokinetic pro valiltramiprosate over 104 weeks of treatment. A completed long-term extension of the trial evaluated the same dose of valiltramiprosate for an additional 104 weeks of treatment for a total of 208 weeks. 3,7,8 About Alzheon Alzheon, Inc. is a clinical-stage biopharmaceutical company dedicated to advancing a diverse portfolio of product candidates and diagnostic assays for individuals affected by Alzheimer’s disease and other neurodegenerative disorders. The company is focused on innovating therapeutic solutions that directly target the underlying pathology of neurodegeneration. Its lead Alzheimer's clinical candidate, valiltramiprosate/ALZ-801 , is a first-in-class oral agent currently in Phase 3 clinical development as a potentially disease-modifying treatment for Alzheimer’s disease. Valiltramiprosate is an orally administered small molecule shown in preclinical studies to completely inhibit the formation of neurotoxic soluble amyloid oligomers. Its well-differentiated follow-on candidate, ALZ-507, is a once daily oral therapy designed to inhibit the formation of amyloid oligomers while also correcting the high risk APOE4 gene. Leveraging clinical expertise and a robust technology platform, Alzheon pursues drug discovery and development using a precision medicine approach that incorporates individual genetic and biomarker pro aiming to advance therapies with meaningful benefits for patients. Alzheon Scientific Publications 1 Abushakra S, et al: Hippocampal Atrophy on Magnetic Resonance Imaging as a Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Symptomatic Alzheimer’s Disease: Synthesis of Evidence from Observational and Interventional Trials, CNS Drugs 2026; 40(2): 199-214. 2 Abushakra S, et al: Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer’s Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial , Drugs 2025; 85(11): 1455-1472. 3 Pearson D, et al: Polymorph Analysis of ALZ-801 (Valiltramiprosate), a Valine-Conjugated Oral Prodrug of Tramiprosate in Late-Stage Clinical Development for Alzheimer’s Disease, Journal of Chemical Crystallography 2025; 55, 206-215. 4 Hey JA, et al: Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a Two-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer’s Disease, Clinical Pharmacokinetics 2025; 64(3): 407-424. 5 Aye S, et al: Point of View: Challenges in Implementation of New Immunotherapies for Alzheimer’s Disease, The Journal of Prevention of Alzheimer’s Disease 2025;12(1):100022. 6 Abushakra S, et al: APOLLOE4 Phase 3 Study of Oral ALZ-801/Valiltramiprosate in APOE ε 4/ ε 4 Homozygotes with Early Alzheimer’s Disease: Trial Design and Baseline Characteristics, Alzheimer’s & Dementia 2024; 10(3): e12498. 7 Tolar M, et al: The Single Toxin Origin of Alzheimer’s Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention, International Journal of Molecular Sciences 2024; 25(5), 2727. 8 Hey JA, et al: Analysis of Cerebrospinal Fluid, Plasma β Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease Using Quantitative Systems Pharmacology Model, Drugs 2024; 84(7), 825-839. 9 Hey JA, et al: Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single Arm, Open Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer’s Disease, Drugs 2024; 84(7), 811-823. 10 Tolar M, et al: Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression , International Journal of Molecular Sciences 2021; 22(12), 6355. 11 Abushakra S, et al: APOE ε4/ε4 Homozygotes with Early Alzheimer’s Disease Show Accelerated Hippocampal Atrophy and Cortical Thinning that Correlates with Cognitive Decline , Alzheimer’s & Dementia 2020; 6(1): e12117. 12 Tolar M, et al: Aducanumab, Gantenerumab, BAN2401, and ALZ-801—the First Wave of Amyloid-Targeting Drugs for Alzheimer’s Disease with Potential for Near Term Approval, Alzheimer’s Research & Therapy 2020; 12(1): 95. 13 Tolar M, et al: The Path Forward in Alzheimer’s Disease Therapeutics: Reevaluating the Amyloid Cascade Hypothesis , Alzheimer’s & Dementia 2020; 16(11):1553-1560. 14 Hey JA, et al: Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain , CNS Drugs 2018; 32(9): 849-861. 15 Hey JA, et al: Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease , Clinical Pharmacokinetics 2018; 57(3): 315-333. 16 Abushakra S, et al: Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification Potential , Journal of Prevention of Alzheimer’s Disease 2017; 4(3): 149-156. 17 Kocis P, et al: Elucidating the A β 42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods , Pharmacokinetic and Clinical Data , CNS Drugs 2017; 31(6): 495-509. 18 Abushakra S, et al: Clinical Benefits of Tramiprosate in Alzheimer’s Disease Are Associated with Higher Number of APOE4 Alleles: The “APOE4 Gene-Dose Effect,” Journal of Prevention of Alzheimer’s Disease 2016; 3(4): 219-228. Contacts Media Contact Yasemin Khakian, Alzheon, Inc. 508.808.2301 yasemin.khakian@alzheon.com Investor Contact Erwan de Naurois, Alzheon, Inc. 802.735.8789 erwan.denaurois@alzheon.com

一、阿尔茨海默症小鼠造模：痴呆研究的核心临床前平台阿尔茨海默症（Alzheimer's Disease, AD）是最常见的神经退行性疾病，全球患者超过5500万，随着人口老龄化加剧，这一数字预计到2050年将突破1.5亿。AD的核心病理特征包括β-淀粉样蛋白（Aβ）沉积形成的细胞外老年斑、Tau蛋白过度磷酸化形成的细胞内神经原纤维缠结、突触丢失及神经元死亡，最终导致进行性认知功能衰退。目前临床可用的胆碱酯酶抑制剂（多奈哌齐、卡巴拉汀）和NMDA受体拮抗剂（美金刚）仅能短暂缓解症状，无法阻止疾病进展，开发能够延缓或逆转AD病理进程的疾病修饰治疗药物（DMTs）已成为全球神经科学领域最紧迫的挑战之一。在这一背景下，阿尔茨海默症小鼠造模凭借其神经系统的高度保守性、基因编辑技术的成熟性以及病理进程的可控性，成为AD机制研究、药物筛选及治疗策略评估不可或缺的黄金标准临床前工具。通过转基因过表达、基因敲入、化学诱导或衰老加速等手段，研究者可在小鼠中成功复制出从Aβ沉积到认知障碍的完整病理谱系，为阿尔茨海默症小鼠造模的广泛应用奠定了坚实基础。二、为什么选择小鼠构建阿尔茨海默症模型？1. 神经系统与AD病理的高度保守性小鼠大脑在解剖结构、神经元类型、突触可塑性、神经递质系统及Aβ代谢通路方面与人类高度同源。在阿尔茨海默症小鼠造模中，Aβ沉积、Tau病理、神经炎症、突触丢失及认知障碍等核心病理特征，与临床AD患者的病理改变高度一致。特别是小鼠的APP（淀粉样前体蛋白）、PSEN1（早老素1）及MAPT（Tau蛋白）基因序列与人类具有高度同源性，使得转基因模型能够精准模拟家族性AD的遗传机制。2. 基因编辑技术精准可控小鼠拥有最成熟的基因编辑技术体系，包括转基因、基因敲除、基因敲入及条件性基因修饰。在阿尔茨海默症小鼠造模中，可精确控制致病基因的表达水平、时空特异性及突变类型，构建从单基因到多基因、从单病理到复合病理的系列模型，满足不同研究目的的需求。3. 认知行为评价技术成熟现代阿尔茨海默症小鼠造模评价已整合Morris水迷宫、新物体识别、恐惧条件化、Y迷宫、T迷宫及社交行为等多种认知测试，能够系统评估空间记忆、识别记忆、联合记忆及工作记忆等认知域，与人类AD的认知损害特征高度对应。4. 成本与伦理优势相比非人灵长类动物，小鼠饲养成本低、繁殖快、样本量充足，且符合3R原则。在阿尔茨海默症小鼠造模中，单批次实验可完成多组药物或干预措施的平行比较，兼顾科学严谨性与研发经济性。三、阿尔茨海默症小鼠造模的核心技术方法1. 转基因淀粉样蛋白模型转基因淀粉样蛋白模型是阿尔茨海默症小鼠造模中应用最广泛的类型，通过过表达人源突变APP或PSEN1基因，驱动Aβ过度产生和沉积：APP/PS1双转基因模型：将携带瑞典突变（K670N/M671L）的人源APP基因与携带ΔE9缺失突变的PSEN1基因共同转入小鼠，3-4月龄开始出现Aβ沉积，6-8月龄形成明显老年斑，伴胶质细胞活化及轻度认知障碍。该模型是研究Aβ病理及评估Aβ清除策略（如抗Aβ抗体）的经典阿尔茨海默症小鼠造模；5xFAD模型：携带5个家族性AD突变（APP瑞典、佛罗里达I716V、伦敦V717I；PSEN1 M146L、L286V），Aβ沉积更早（2月龄）、更密集，认知障碍进展更快，适用于快速药物筛选；APPswe/PS1dE9模型：与APP/PS1类似，但转基因整合位点不同，Aβ沉积和认知表型稳定，是评估Aβ疫苗及免疫治疗的常用模型；Tg2576模型：仅过表达APP瑞典突变，Aβ沉积较晚（9-12月龄），但病理进程更接近散发性AD的自然进展。2. Tau病理模型Tau病理是AD的另一核心特征，与认知衰退密切相关：P301S Tau转基因模型：过表达携带P301S突变的人源Tau基因，形成神经原纤维缠结、轴突变性及运动障碍，适用于研究Tau病理传播及Tau靶向治疗；rTg4510模型：可诱导性表达P301L突变Tau，通过Doxycycline调控Tau表达，可研究Tau病理的可逆性；3xTg-AD模型：同时携带APP瑞典、Tau P301L及PS1 M146V突变，同时呈现Aβ沉积、Tau病理及突触功能障碍，是研究Aβ-Tau交互作用的复合阿尔茨海默症小鼠造模。3. Aβ寡聚体注射模型Aβ寡聚体被认为是AD最主要的神经毒性形式：Aβ1-42寡聚体海马注射模型：将人工合成的Aβ1-42寡聚体立体定位注射于海马CA1区或侧脑室，快速诱导局部Aβ沉积、突触丢失及记忆障碍。该模型操作简便、周期短（2-4周），是评估Aβ毒性机制及急性干预策略的常用阿尔茨海默症小鼠造模；Aβ1-40/1-42纤维注射模型：注射预聚集的Aβ纤维，诱导更持久的病理改变，适用于研究Aβ种子效应及病理传播。4. 化学与衰老诱导模型D-半乳糖联合AlCl₃模型：长期皮下注射D-半乳糖（诱导氧化应激和糖基化）联合AlCl₃灌胃（诱导神经毒性），构建散发性AD样模型，伴认知障碍、Aβ样沉积及Tau过度磷酸化；链脲佐菌素（STZ）脑内注射模型：脑内注射STZ破坏胰岛素信号，诱导脑胰岛素抵抗、Aβ沉积及认知障碍，模拟3型糖尿病（脑型糖尿病）假说；自然衰老模型：利用18-24月龄老年C57BL/6小鼠，其自然出现认知衰退、突触丢失及轻度Aβ沉积，适用于研究年龄相关认知障碍；SAMP8快速衰老小鼠：自发性衰老模型，8月龄即出现明显认知障碍、Aβ沉积及氧化应激，造模周期短。5. 基因编辑与复合模型APP敲入模型：将人源APP突变基因敲入小鼠APP基因座，避免转基因过表达的随机整合和拷贝数效应，更精准模拟家族性AD；APOE4敲入模型：APOE4是散发性AD最强遗传风险因子，APOE4敲入小鼠可研究脂质代谢与Aβ清除的交互作用；TREM2突变模型：TREM2是小胶质细胞表面受体，其突变增加AD风险，适用于研究神经免疫机制。四、阿尔茨海默症小鼠造模的评价指标体系1. 认知行为学评估Morris水迷宫：评估空间参考记忆和学习能力，记录逃避潜伏期、平台穿越次数、目标象限停留时间；新物体识别实验（NOR）：评估识别记忆，计算辨别指数（DI）=（探索新物体时间-探索熟悉物体时间）/总探索时间；恐惧条件化：评估联合记忆，包括情境恐惧（海马依赖）和线索恐惧（杏仁核依赖）；Y迷宫/T迷宫：评估工作记忆和自发交替行为；** Barnes迷宫**：评估空间记忆，与水迷宫互补，避免游泳应激；社交行为测试：评估社交记忆和社交新颖性偏好。2. Aβ病理与沉积免疫组化/免疫荧光：6E10、4G8、82E1等抗Aβ抗体标记老年斑，定量斑块数量、面积及分布（皮层、海马、丘脑）；Thioflavin S/T染色：标记致密核心老年斑；Aβ ELISA：脑组织匀浆中可溶性Aβ40、Aβ42及不溶性Aβ水平；Aβ寡聚体检测：特异性寡聚体抗体（如A11、OC）Western blot或ELISA。3. Tau病理与神经退变AT8免疫组化：检测Ser202/Thr205磷酸化Tau；PHF-1免疫组化：检测Ser396/404磷酸化Tau；Gallyas银染：标记神经原纤维缠结；Tau ELISA：总Tau及磷酸化Tau水平；神经元标志物：NeuN免疫组化定量存活神经元数量；突触标志物：Synaptophysin、PSD-95、MAP2免疫组化/Western blot。4. 神经炎症与胶质细胞活化Iba1免疫组化：标记活化的小胶质细胞，定量细胞数量及形态变化；GFAP免疫组化：标记活化的星形胶质细胞；CD68/ED1：标记吞噬性小胶质细胞/巨噬细胞；炎症因子：IL-1β、IL-6、TNF-α、TGF-β、CCL2、CX3CL1 ELISA或qPCR；补体系统：C1q、C3、C3aR检测。5. 突触功能与神经可塑性长时程增强（LTP）：海马脑片电生理记录，评估突触可塑性；长时程抑制（LTD）：评估突触抑制机制；微型兴奋性突触后电流（mEPSC）：评估突触传递功能；脑电图（EEG）：记录自发放电及癫痫样活动。6. 分子机制与多组学分析通过转录组测序、蛋白质组学、代谢组学及单细胞测序，在阿尔茨海默症小鼠造模中解析：APP加工通路（BACE1、PSEN1、Nicastrin、APH-1、PEN-2）；Aβ清除机制（IDE、Neprilysin、MMP9、LRP1、RAGE）；Tau磷酸化激酶（GSK-3β、CDK5、ERK2、JNK）及磷酸酶（PP2A）；自噬-溶酶体通路（LC3、p62、LAMP1、TFEB）；线粒体功能障碍（Drp1、Mfn2、PGC-1α、ATP产量）；表观遗传调控（DNA甲基化、组蛋白乙酰化、miRNA）。五、阿尔茨海默症小鼠造模的主要应用领域1. 抗Aβ疾病修饰药物研发在阿尔茨海默症小鼠造模中，可系统评估以下候选药物的抗Aβ效力：BACE1抑制剂：如Verubecestat、Lanabecestat（减少Aβ生成）；γ-分泌酶抑制剂/调节剂：如Semagacestat、Avagacestat（调节APP切割）；抗Aβ单克隆抗体：如Aducanumab、Lecanemab、Donanemab（促进Aβ清除）；Aβ聚集抑制剂：如Tramiprosate、ALZ-801（阻止寡聚体形成）；Aβ疫苗：如AN1792、CAD106（主动免疫诱导Aβ抗体）。通过量化Aβ沉积减少、认知改善及神经炎症减轻，在早期研发阶段即完成药效学评价。2. Tau靶向治疗研究Tau聚集抑制剂（如亚甲蓝衍生物LMTX）、抗Tau抗体（如Semorinemab、Zagotenemab）及Tau去磷酸化策略，可在阿尔茨海默症小鼠造模中评估其对Tau病理传播、神经元保护及认知功能的改善作用。3. 神经炎症与免疫调节小胶质细胞调节剂（TREM2激动剂、CSF1R抑制剂）、补体抑制剂及NLRP3炎症小体抑制剂，可在阿尔茨海默症小鼠造模中评估其对神经炎症的调控及认知保护效果。4. 中药复方与天然产物现代化石杉碱甲（Huperzine A）、银杏叶提取物（EGb761）、人参皂苷、姜黄素、白藜芦醇、丹参酮及复方（如黄连解毒汤、当归芍药散）等，可通过阿尔茨海默症小鼠造模现代化验证其抑制Aβ聚集、抗Tau磷酸化、抗炎抗氧化及改善认知的生物学效应。5. 功能性食品与营养干预Omega-3脂肪酸（DHA/EPA）、维生素E、维生素D、叶酸、维生素B12、益生菌及地中海饮食模式等，可在阿尔茨海默症小鼠造模中评估其通过"肠-脑轴"改善认知的系统性效应。六、百环生物：阿尔茨海默症小鼠造模的专业服务平台在神经退行性疾病临床前研究领域，百环生物建立了完善的技术服务体系，为制药企业、科研院所、生物技术公司及健康产品企业提供从模型构建到数据交付的一站式阿尔茨海默症小鼠造模解决方案。标准化AD模型平台百环生物已成功建立多种成熟的阿尔茨海默症小鼠造模体系，包括：APP/PS1双转基因模型（经典Aβ病理模型，3-4月龄Aβ沉积，6-8月龄认知障碍）5xFAD快速进展模型（早发Aβ沉积，2月龄病理，适用于快速筛选）3xTg-AD复合病理模型（Aβ+Tau双病理，研究病理交互）P301S Tau转基因模型（纯Tau病理，研究缠结机制）Aβ1-42寡聚体海马注射模型（急性Aβ毒性，2-4周认知障碍）D-半乳糖/AlCl₃散发性AD模型（非转基因，模拟氧化应激）SAMP8快速衰老模型（8月龄认知障碍，造模周期短）APP敲入精准模型（内源性启动子，避免过表达 artifacts）所有模型均经过严格的病理表型验证与阳性药物对照测试（如多奈哌齐、美金刚、Aducanumab类似物），确保Aβ沉积、Tau病理、神经炎症及认知障碍指标的稳定性与可重复性。多维度评价技术体系百环生物配备先进的神经行为学与分子病理平台，可在阿尔茨海默症小鼠造模中完成：Morris水迷宫、新物体识别、恐惧条件化、Y迷宫、Barnes迷宫认知测试；脑组织Aβ免疫组化（6E10、4G8）及老年斑定量分析；Thioflavin S致密核心斑块染色；Aβ40/Aβ42 ELISA及寡聚体Western blot；AT8/PHF-1 Tau磷酸化免疫组化及神经原纤维缠结定量；NeuN神经元存活计数及Synaptophysin/PSD-95突触标志物检测；Iba1/CD68小胶质细胞活化及GFAP星形胶质细胞活化分析；血清/脑组织炎症因子（IL-1β、IL-6、TNF-α）ELISA；海马脑片LTP电生理记录；转录组学/蛋白质组学/代谢组学/单细胞测序机制研究支持。药物筛选与机制研究服务百环生物支持基于阿尔茨海默症小鼠造模的抗Aβ药物、Tau靶向药物、神经炎症调节剂、干细胞治疗、基因治疗、中药复方、天然产物及功能性食品的系统评价、量效关系分析、联合用药优化及作用机制探索。专业团队协助客户设计合理的基因型选择、给药时机（预防性/治疗性）及评价终点，并提供符合NMPA/FDA申报要求的完整数据包。严格的质量与合规管理百环生物遵循实验动物伦理规范与数据完整性管理原则，所有阿尔茨海默症小鼠造模实验均设置野生型同窝对照、模型对照及阳性药对照，认知测试由经过专业培训的人员在标准化环境中盲法执行，电生理记录由专业技术人员操作，原始数据、视频记录、电生理数据及统计分析报告完整归档，确保研究结果的科学可信度与可追溯性。全流程项目支持从项目咨询、AD模型选择、实验方案设计、阿尔茨海默症小鼠造模构建、认知监测、病理评价到最终报告撰写，百环生物提供全流程技术支持与项目管理服务，助力客户高效推进AD疾病修饰药物研发、神经保护机制研究及认知健康产品开发。七、结语阿尔茨海默症小鼠造模以其神经系统的高度保守性、病理进程的可控性及基因编辑的精准性，正在成为神经退行性疾病研究与抗痴呆药物开发领域不可或缺的技术工具。无论是解析Aβ寡聚体的神经毒性机制，还是加速新型抗Aβ免疫疗法从实验室到临床的转化，选择一家技术扎实、体系完善的实验服务平台都是确保研究质量与研发效率的关键。百环生物深耕神经退行性疾病临床前研究领域，以标准化的阿尔茨海默症小鼠造模平台、多维度的评价技术体系与严谨的质量管理，为每一位合作伙伴提供高质量的临床前研究服务，共同推动阿尔茨海默症等神经退行性疾病的精准防治与创新疗法开发。返回搜狐，查看更多