阿尔茨海默病：从分子发病机制到疾病修饰治疗及在老龄化人群中的临床实施

文献信息

中文摘要

阿尔茨海默病（AD）是全球痴呆症的首要病因，对65岁以上人群的影响尤为突出，并给全球医疗系统和照护者带来越来越沉重的负担。数十年来，其管理依赖于症状性药物——胆碱酯酶抑制剂和美金刚——这些药物可提供适度的认知获益，但不能改变疾病进展。近期获批的抗淀粉样蛋白单克隆抗体lecanemab（2023年）和donanemab（2024年）代表了范式转变，提供了首批通过靶向潜在淀粉样蛋白-β病理而适度但显著延缓临床衰退的疗法。然而，这些进展伴随着重要的安全性担忧，特别是淀粉样蛋白相关影像学异常、高昂的费用，以及在长期临床意义和公平可及性方面尚未解决的问题。这篇综合性综述整合了AD全谱系的当前知识，涵盖分子病理生理学（淀粉样蛋白级联、tau过度磷酸化和神经炎症）、遗传结构（家族性突变和APOE介导的风险）、不断演变的基于生物标志物的诊断框架、已确立的症状性治疗以及新获批的疾病修饰药物。我们进一步审视了新兴治疗策略，包括靶向tau的疗法、针对神经炎症的方法、多靶点和联合策略、药物递送创新以及临床前人群中的预防试验。通篇我们批判性地评估证据，承认争议和局限性，同时识别有前景的未来方向。重要的是，将这些诊断和遗传学进展整合到老年照护环境中提出了独特的实施挑战，因为老龄化人群常面临合并症、多重用药以及获得专科诊断基础设施的机会有限。随着AD治疗进入新时代，将药物干预与生物标志物指导的患者选择、严格的安全性监测以及可改变风险因素管理相结合，对于优化老龄化人群的结局至关重要。

英文摘要

Alzheimer's disease (AD) is the leading cause of dementia worldwide, disproportionately affecting individuals over 65 years of age and imposing a rapidly escalating burden on healthcare systems and caregivers globally. For decades, management relied on symptomatic agents-cholinesterase inhibitors and memantine-that provide modest cognitive benefits without altering disease progression. The recent approvals of the anti-amyloid monoclonal antibodies lecanemab (2023) and donanemab (2024) represent a paradigm shift, offering the first therapies that modestly but significantly slow clinical decline by targeting the underlying amyloid-β pathology. However, these advances are accompanied by important safety concerns, particularly amyloid-related imaging abnormalities, substantial costs, and unresolved questions regarding long-term clinical meaningfulness and equitable access. This comprehensive review synthesizes current knowledge across the full spectrum of AD, encompassing molecular pathophysiology (amyloid cascade, tau hyperphosphorylation, and neuroinflammation), genetic architecture (familial mutations and APOE-mediated risk), evolving biomarker-based diagnostic frameworks, established symptomatic treatments, and newly approved disease-modifying agents. We further examine emerging therapeutic strategies, including tau-targeted therapies, neuroinflammation-directed approaches, multi-target and combination strategies, drug delivery innovations, and prevention trials in preclinical populations. Throughout, we critically evaluate the evidence, acknowledging controversies and limitations while identifying promising future directions. Importantly, integrating these diagnostic and genetic advances into geriatric care settings presents unique implementation challenges, as aging populations often face comorbidities, polypharmacy, and limited access to specialized diagnostic infrastructure. As AD therapeutics enter a new era, integrating pharmacological interventions with biomarker-guided patient selection, rigorous safety monitoring, and modifiable risk factor management will be essential for optimizing outcomes in aging populations.