Mendes Augusto J, Ribaldi Federica, Pievani Michela, Boccalini Cecilia, Garibotto Valentina, Frisoni Giovanni B
Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Switzerland.
Geneva Memory Center, Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Switzerland.
Neurology. 2025 Jun 10;104(11):e213675. doi: 10.1212/WNL.0000000000213675. Epub 2025 May 13.
The amyloid cascade hypothesis posits that Alzheimer disease (AD) progresses from amyloid deposition to tau deposition, neurodegeneration, and eventually cognitive impairment and is the foundation of the revised criteria of Alzheimer's Association Workgroup 2024 (AA-2024). To account for copathologies and cognitive resilience that affect the penetrance of the AD cascade, AA-2024 introduced a 2-dimensional biological-clinical staging framework. We aimed to estimate the proportion of persons along the AD continuum whose biological and clinical trajectories align with the amyloid cascade.
Cross-sectional data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were tested in the 4 × 4 biological/clinical staging matrix adapted from the AA-2024 criteria. Biological stages were defined by amyloid and tau-PET burden: stage A (amyloid positivity, A+), stage B (medial temporal tau, A+/T+), stage C (moderate neocortical tau, A+/T+), and stage D (high neocortical tau, A+/T+). Clinical stages were cognitively unimpaired (stage 1), subtle cognitive impairment (stage 2), mild cognitive impairment (stage 3), and dementia (stages 4-6). Tau-PET cutoffs were defined through the implementation of 5 distinct methods. Participants were categorized into (1) compliant with the amyloid cascade (matrix diagonal), (2) resilient (advanced biological stage-early clinical stage), and (3) copathologic (early biological stage-advanced clinical stage). Observed distributions were compared with hypothetical scenarios with zero and high amyloid cascade penetrance using the χ test, and differences among the 5 methods were tested using the Cochran Q test.
Two-hundred and fifty-six amyloid-positive individuals (mean age: 72.7 years; 51% female) from the ADNI cohort were considered. The proportion of participants compliant with the amyloid cascade was between 31% (95% CI 25%-37%) and 36% (95% CI 30%-42%) depending on the tau-PET cutoff method. The observed number of individuals compliant with the amyloid cascade was higher than in the zero-penetrance scenario but lower than in the high-penetrance distribution ( < 0.01). The proportion of copathologic (17%-63%) and resilient (6%-52%) individuals varied widely by tau-PET cutoff ( < 0.001).
Only approximately one-third of persons with an AA-2024 diagnosis of AD complied with the predictions of the amyloid cascade hypothesis. These results suggest the heterogeneity in how clinical symptoms and pathology are coupled along the AD continuum, which has significant implications for interpreting completed antiamyloid clinical trials and designing future studies.
淀粉样蛋白级联假说认为，阿尔茨海默病（AD）从淀粉样蛋白沉积发展为tau蛋白沉积、神经退行性变，并最终导致认知障碍，这是2024年阿尔茨海默病协会工作组修订标准（AA - 2024）的基础。为了解释影响AD级联反应外显率的共病和认知弹性，AA - 2024引入了一个二维生物 - 临床分期框架。我们旨在估计处于AD连续统中的人群中，其生物和临床轨迹与淀粉样蛋白级联相一致的比例。
阿尔茨海默病神经影像倡议（ADNI）队列的横断面数据在根据AA - 2024标准改编的4×4生物/临床分期矩阵中进行测试。生物阶段由淀粉样蛋白和tau - PET负荷定义：A期（淀粉样蛋白阳性，A +），B期（内侧颞叶tau蛋白，A + /T +），C期（中度新皮质tau蛋白，A + /T +），D期（高新皮质tau蛋白，A + /T +）。临床阶段为认知未受损（1期）、轻微认知障碍（2期）、轻度认知障碍（3期）和痴呆（4 - 6期）。tau - PET临界值通过5种不同方法的实施来定义。参与者被分为（1）符合淀粉样蛋白级联（矩阵对角线），（2）有弹性（生物阶段进展 - 临床阶段早期），（3）共病（生物阶段早期 - 临床阶段进展）。使用χ检验将观察到的分布与淀粉样蛋白级联外显率为零和高外显率的假设情景进行比较，并使用 Cochr an Q检验测试5种方法之间的差异。
考虑了ADNI队列中的256名淀粉样蛋白阳性个体（平均年龄：72.7岁；51%为女性）。根据tau - PET临界值方法，符合淀粉样蛋白级联的参与者比例在31%（95%CI 25% - 37%）至36%（95%CI 30% - 至42%）之间。观察到的符合淀粉样蛋白级联的个体数量高于零外显率情景，但低于高外显率分布（<0.01）。共病个体（17% - 63%）和有弹性个体（6% - 52%）的比例因tau - PET临界值不同而有很大差异（<0.001）。
在AA - 2024诊断为AD的人群中，只有大约三分之一符合淀粉样蛋白级联假说的预测。这些结果表明，在AD连续统中临床症状和病理的耦合方式存在异质性，这对解释已完成的抗淀粉样蛋白临床试验和设计未来研究具有重要意义。
