We were particularly interested in the 2024 Revised Criteria for Diagnosis and Staging of Alzheimer's Disease (AD) from the Alzheimer's Association (AA) workgroup. These criteria seek to update the biological definition of AD, originally introduced in 2011, to inform both research and clinical care.¹ The proposal of a formal transition from a clinico-biological to a purely biological disease definition marks a significant historical and epistemological shift,² placing greater emphasis on the threshold of pathologic changes that distinguish between normality and disease, without relying on clinical factors. However, establishing this threshold and the corresponding pathological anchors poses various challenges.

The Revised Criteria define AD as “a biological process that begins with the appearance of AD neuropathologic change.”¹ According to the National Institute on Aging–AA guidelines for the neuropathologic assessment of AD,³ the very first AD neuropathologic changes correspond to a Thal amyloid beta (Aβ) plaque score of 1, which includes neuritic and non-neuritic plaques, in the absence or presence of neurofibrillary tangles. Therefore, the Revised Criteria implicitly establish the theoretical threshold between normality and AD based exclusively on the presence of Aβ aggregates, regardless of neurofibrillary tangles. The Revised Criteria are the first to anchor the AD definition at a biological model recognizing the precedence of Aβ over tau pathology: the Aβ cascade hypothesis.⁴

The Revised Criteria establishes a positive visual read on an Aβ positron emission tomography (PET) scan, along with several “Core 1 Biomarkers” validated against Aβ PET, as the new gold standard for AD diagnosis. To justify that the operationalization of this definition of AD does not deviate from the historical definition based on Aβ plaques and tangles, the authors claim that Aβ positivity on PET reflects not only Aβ plaques but also, in the majority of cases, Braak stages ≥ III. To justify this statement, the authors used data from the National Alzheimer's Coordinating Center (NACC; n = 252) and the Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program (n = 123) neuropathologic cohorts. They found that 74% and 87%, respectively, of the unimpaired individuals with moderate/frequent Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores of neuritic Aβ plaques also had Braak stage ≥ III, supporting their claim that Aβ PET positivity (moderate/frequent CERAD scores) corresponds to both plaques and tangles. However, because the prevalence of Braak stages ≥ III increases with age independent of Aβ,⁵ we questioned whether the advanced average age of the individuals included in the neuropathologic cohorts used by the authors (≈ 86.5 years in the NACC sample) could have contributed to the high proportion of individuals with Braak stages ≥ III. A logistic regression analysis in the NACC sample of unimpaired individuals (Clinical Dementia Rating = 0 within 1 year of death, n = 154) with moderate/frequent CERAD scores shows that the proportion of individuals with Braak stages ≥ III significantly increased with age (b = 0.062 y⁻¹, P = 0.005, Figure 1A). To estimate the actual proportion of Aβ PET–positive unimpaired individuals with Braak stages ≥ III worldwide, we combined previously published estimates of the age distribution of Aβ PET–positive cognitively unimpaired individuals⁶ with our estimates of the age-specific prevalence of Braak stages ≥ III in this population. We found that, out of the previously estimated ≈ 315 million Aβ PET–positive unimpaired persons aged > 50 worldwide, only 113 million (36%, 95% confidence interval [21% to 58%]) have Braak stages III through VI (Figure 1B). Therefore, the operationalization of the earliest stages of the Revised Criteria, involving cognitively unimpaired individuals, will result in a majority (≈ 64%) of none-to-low levels of tau pathology and low levels of AD neuropathologic change. These findings contradict the Revised Criteria's statement on the intermediate-to-high levels of pathological correlates of Aβ PET positivity in the cognitively unimpaired population.

In summary, the early stages of the Revised Criteria are primarily anchored at Aβ aggregates and not tangles. The Revised Criteria challenge long-standing perspectives emphasizing the combination of Aβ and tau pathology at high levels as defining features of AD.² The present discussion highlights the difficulties in establishing anchors and thresholds when relying on a purely biological disease concept without clinical context. The example of neuropathologists moving away from setting thresholds to define AD⁷ and instead setting mere levels of AD neuropathologic changes³ illustrates the inherent challenge of relying purely on a pathological threshold for disease definition.

我们对阿尔茨海默病协会 （AA） 工作组的 2024 年阿尔茨海默病 （AD） 诊断和分期修订标准特别感兴趣。这些标准旨在更新最初于 2011 年引入的 AD 的生物学定义，为研究和临床护理提供信息。¹ 从临床生物学疾病定义正式过渡到纯生物学疾病定义的提议标志着一个重大的历史和认识论转变，² 更加强调区分正常和疾病的病理变化阈值，而不依赖于临床因素。然而，建立这个阈值和相应的病理锚点带来了各种挑战。

修订标准将 AD 定义为“从 AD 神经病理变化的出现开始的生物过程”。¹ 根据美国国家老龄化研究所 - AA AD 神经病理学评估指南，³ 最初的 AD 神经病理学变化对应于 Thal β 淀粉样蛋白 （Aβ） 斑块评分 1，其中包括神经炎和非神经炎斑块，在没有或存在神经原纤维缠结的情况下。因此，修订标准隐含地建立了正常和 AD 之间的理论阈值，仅基于 Aβ 聚集体的存在，而不考虑神经原纤维缠结。修订标准首次将 AD 定义锚定在承认 Aβ 优先于 tau 病理学的生物学模型上：Aβ 级联假说。⁴

修订后的标准在 Aβ 正电子发射断层扫描 （PET） 扫描上建立了阳性视觉读数，以及针对 Aβ PET 验证的几个“核心 1 生物标志物”，作为 AD 诊断的新金标准。为了证明 AD 定义的实施没有偏离基于 Aβ 斑块和缠结的历史定义，作者声称 PET 上的 Aβ 阳性不仅反映了 Aβ 斑块，而且在大多数情况下还反映了 Braak ≥ III 期。为了证明这一说法的合理性，作者使用了来自国家阿尔茨海默病协调中心 （NACC;n = 252） 和亚利桑那州衰老和神经退行性疾病研究以及大脑和身体捐赠计划 （n = 123） 神经病理学队列。他们发现，神经炎 Aβ 斑块的中度/频繁建立阿尔茨海默病登记联盟 （CERAD） 评分的中度/频繁个体中，分别有 74% 和 87% 的个体也具有 Braak ≥ III 期，支持他们的说法，即 Aβ PET 阳性（中度/频繁 CERAD 评分）对应于斑块和缠结。然而，由于 Braak III ≥期的患病率随着年龄的增加而增加，与 Aβ 无关，⁵ 我们质疑作者使用的神经病理学队列中包括的个体的高级平均年龄（NACC 样本中≈ 86.5 岁）是否可能导致 Braak ≥ III 期个体的高比例。对具有中度/频繁 CERAD 评分的未受损个体（死亡后 1 年内临床痴呆评分 = 0，n = 154）的 NACC 样本进行的 logistic 回归分析显示，Braak ≥ III 期个体的比例随着年龄的增长而显着增加 （b = 0.062 ^y-1，P = 0。 005，图 1A）。为了估计全球 Aβ PET 阳性未受损个体≥ Braak III 期的实际比例，我们将先前发表的 Aβ PET 阳性认知未受损个体的年龄分布估计值⁶ 与我们对 Braak ≥ 期 III 年龄特异性患病率的估计值相结合该人群。我们发现，在先前估计的 3.15 亿 Aβ PET 阳性非受损者中，年龄在 > 50 ≈，只有 1.13 亿 （36%，95% 置信区间 [21% 至 58%]）患有 Braak III 至 VI 期（图 1B）。因此，修订标准最早阶段的实施，涉及认知未受损的个体，将导致大多数 （≈ 64%） 无或低水平的 tau 病理和低水平的 AD 神经病理变化。这些发现与修订标准关于认知未受损人群中 Aβ PET 阳性中度至高度病理相关性的声明相矛盾。

总之，修订标准的早期阶段主要锚定在 Aβ 聚集体，而不是缠结。修订后的标准挑战了长期存在的观点，即强调 Aβ 和 tau 病理学在高水平上的结合是 AD 的定义特征.² 目前的讨论强调了在没有临床背景的情况下依赖纯生物疾病概念时建立锚点和阈值的困难。神经病理学家不再设定阈值来定义 AD⁷，而是仅仅设定 AD 神经病理学变化的水平³ 的例子说明了纯粹依赖病理阈值来定义疾病的固有挑战。