From the Department of Biostatistics and Epidemiology (J.Q.), University of Massachusetts, Amherst; New York University College of Global Public Health (R.A.B.), New York City; Department of Neurology (B.T.H., A.S.-P.), Massachusetts General Hospital, Boston; Massachusetts Alzheimer's Disease Research Center (B.T.H., A.S.-P.), Charlestown; and Harvard Medical School (B.T.H., A.S.-P.), Boston, MA.
Neurology. 2021 May 11;96(19):e2414-e2428. doi: 10.1212/WNL.0000000000011883. Epub 2021 Mar 26.
To test the hypothesis that the genotype is a significant driver of heterogeneity in Alzheimer disease (AD) clinical progression, which could have important implications for clinical trial design and interpretation.
We applied novel reverse-time longitudinal models to analyze the trajectories of Clinical Dementia Rating Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores-2 common outcome measures in AD clinical trials-in 1,102 autopsy-proven AD cases (moderate/frequent neuritic plaques and Braak tangle stage III or greater) from the National Alzheimer's Coordinating Center Neuropathology database resembling participants with mild to moderate AD in therapeutic clinical trials.
ε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than ε3/ε3 carriers (2.12 points per year vs 1.44 points per year) and ≈1.3 times faster increase than ε2 carriers (1.65 points per year), whereas ε2 vs ε3/ε3 difference was not statistically significant. ε4 carriers had ≈1.1 times faster MMSE decline than ε3/ε3 carriers (-3.45 vs -3.03 points per year) and ≈1.4 times faster decline than ε2 carriers (-2.43 points per year), whereas ε2 carriers had ≈1.2 times slower decline than ε3/ε3 carriers (-2.43 vs -3.03 points per year). These findings remained largely unchanged after controlling for the effect of AD neuropathologic changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies.
Compared to the ε3ε3 reference genotype, the ε2 and ε4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential allele effects on AD and comorbid pathologies. Thus, genotype contributes to the heterogeneity in rate of clinical progression in AD.
检验基因型是阿尔茨海默病（AD）临床进展异质性的重要驱动因素这一假说，这对临床试验设计和解释具有重要意义。
我们应用新的逆时纵向模型分析了 1102 例尸检证实的 AD 病例（中度/频繁神经原纤维缠结和 Braak 缠结 III 期或更高阶段）的临床痴呆评定量表总和框（CDR-SOB）和简易精神状态检查（MMSE）评分-2 种 AD 临床试验中的常见结局指标的轨迹，这些病例来自国家阿尔茨海默病协调中心神经病理学数据库，类似于治疗性临床试验中轻度至中度 AD 的参与者。
ε4 携带者的 CDR-SOB 增加速度比 ε3/ε3 携带者快约 1.5 倍（每年增加 2.12 分，每年增加 1.44 分），比 ε2 携带者快约 1.3 倍（每年增加 1.65 分），而 ε2 与 ε3/ε3 之间的差异无统计学意义。ε4 携带者的 MMSE 下降速度比 ε3/ε3 携带者快约 1.1 倍（每年下降 3.45 分，每年下降 3.03 分），比 ε2 携带者快约 1.4 倍（每年下降 2.43 分），而 ε2 携带者的下降速度比 ε3/ε3 携带者慢约 1.2 倍（每年下降 2.43 分，每年下降 3.03 分）。在控制 AD 神经病理学改变对认知下降速度的影响以及共存病理的存在和严重程度后，这些发现基本保持不变。
与 ε3ε3 参考基因型相比，ε2 和 ε4 等位基因对认知下降速度的影响相反（分别为减缓和加速），这在临床上具有重要意义，并且在很大程度上独立于 等位基因对 AD 和共存病理的不同影响。因此，基因型导致 AD 临床进展率的异质性。
