From the Department of Family Medicine and Public Health (Y.Q., K.M.), Department of Neurosciences (D.M.J., D.P.S., H.H.F.), and Shiley-Marcos Alzheimer's Disease Research Center (D.M.J., D.P.S., H.H.F.), University of California, San Diego, La Jolla.
Neurology. 2019 Aug 20;93(8):e778-e790. doi: 10.1212/WNL.0000000000007967. Epub 2019 Jul 18.
To identify heterogeneity in cognitive profiles of patients with probable Alzheimer disease (AD) who have mild to moderate dementia and satisfy inclusion and exclusion criteria for a typical AD clinical trial, and to determine whether cognitive profiles are systematically related to the clinical course and neuropathologic features of the disease.
Neuropsychological test data from patients with mild to moderate probable AD (n = 4,711) were obtained from the National Alzheimer's Coordinating Center. Inclusion and exclusion criteria usually used in AD clinical trials were applied. Principal component analysis and model-based clustering were used to identify cognitive profiles in a subset of patients with autopsy-verified AD (n = 800) and validated in the overall (nonautopsy) sample and an independent cohort with similar test data. Relationships between cognitive profile, clinical characteristics, and rate of decline were examined with mixed-effects models.
In the autopsy-confirmed sample, 79.6% of patients had a typical AD cognitive profile (greater impairment of episodic memory than other cognitive functions), and 20.4% had an atypical profile (comparable impairment across cognitive domains). Similar results were obtained in the overall (typical 79.8%, atypical 20.2%) and validation (typical 71.8%, atypical 28.2%) samples. Atypicality was associated with younger age, male sex, lower probability of ε4, less severe global dementia, higher depression scores, lower Braak stage at autopsy, and slower cognitive decline.
We can reliably identify distinct cognitive profiles among patients with clinically diagnosed probable AD that are associated with tangle pathology and with different rates of decline. This may have implications for clinical trials in AD, especially therapies targeting tau.
确定轻度至中度痴呆且符合典型 AD 临床试验纳入和排除标准的可能 AD 患者认知特征的异质性，并确定认知特征是否与疾病的临床病程和神经病理学特征有系统的关系。
从国家 AD 协调中心获得轻度至中度可能 AD 患者（n = 4711）的神经心理学测试数据。应用 AD 临床试验中通常使用的纳入和排除标准。在经过尸检证实的 AD 患者亚组（n = 800）中使用主成分分析和基于模型的聚类来识别认知特征，并在整个（非尸检）样本和具有类似测试数据的独立队列中进行验证。使用混合效应模型检查认知特征与临床特征和下降率之间的关系。
在尸检证实的样本中，79.6%的患者具有典型的 AD 认知特征（情节记忆损害大于其他认知功能），20.4%具有非典型特征（认知领域损害相当）。在整个样本（典型 79.8%，非典型 20.2%）和验证样本（典型 71.8%，非典型 28.2%）中也得到了类似的结果。非典型性与年龄较小、男性、ε4 概率较低、全球痴呆程度较轻、抑郁评分较高、尸检时 Braak 分期较低以及认知下降速度较慢有关。
我们可以可靠地识别出临床诊断为可能 AD 的患者中存在的不同认知特征，这些特征与缠结病理学以及不同的下降速度有关。这可能对 AD 的临床试验有影响，特别是针对 tau 的治疗方法。
