Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Bay Area Wellness, Walnut Creek, CA, USA.
J Alzheimers Dis. 2023;96(2):429-437. doi: 10.3233/JAD-230467.
The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.
神经退行性疾病领域在开发有效疗法方面取得的成功极为有限。一个潜在的原因是缺乏能够产生准确预测和最佳治疗靶点的疾病模型。标准临床试验预先确定了单一的治疗方式，而这种方式可能与神经退行性变的主要驱动因素无关。最近使用精准医学方法进行的概念验证临床试验表明，阿尔茨海默病（AD）是一种慢性固有脑炎，会导致网络不足，这为其提供了一个新的模型。针对每位患者认知能力下降的多种潜在原因进行识别和处理，可能是一种更有效的策略。本文综述了在 AD 相关认知能力下降的预防和治疗中采用精准医学方法的基本原理。本文还介绍了最近概念验证临床试验的结果和意义。可能需要开展更大规模患者的随机对照试验，以确立精准医学方案作为认知能力下降预防和治疗的标准护理方案。此外，将这种方法与药物治疗方法相结合，可能会提高治疗效果。然而，要将精准医学方法纳入日常评估和护理以及未来的临床试验中，则需要在试验设计、IRB 考虑、资金考虑、实验室评估、个性化治疗计划、治疗团队以及最终的报销指南方面进行根本性改变。尽管如此，基于 AD 病理生理学新模型的 AD 精准医学方法有望实现迄今为止单一疗法未能实现的目标。
