Bader Ilse, Groot Colin, Van Der Flier Wiesje M, Pijnenburg Yolande A L, Ossenkoppele Rik
Amsterdam Neuroscience, Neurodegeneration, the Netherlands.
Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, the Netherlands.
Neurology. 2025 May 27;104(10):e213603. doi: 10.1212/WNL.0000000000213603. Epub 2025 Apr 28.
Survival estimates for individuals with Alzheimer disease (AD) are informative to understand the disease trajectory, but precise estimates for atypical AD variants are scarce. Atypical AD variants are characterized by nonamnestic phenotypes, an early onset, and lower prevalence of ε carriership, which affect the AD trajectory. We aimed to provide survival estimates for posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), and behavioral AD (bvAD) and to evaluate the effect of these atypical AD diagnoses beyond known mortality determinants.
From the Amsterdam Dementia Cohort, we retrospectively selected patients with biomarker-confirmed sporadic AD presenting at the memory clinic in the mild cognitive impairment or dementia stage. Patients were classified into atypical AD phenotypes (PCA, lvPPA, bvAD; multidisciplinary consensus and retrospective case finding) and a typical AD reference group (excluding unclassifiable atypical presentations or unconfirmed future AD dementia). Survival estimates from the first visit to death/censoring (Central Public Administration) were determined (Kaplan-Meier analysis) and compared (log-rank tests) across diagnostic groups. To assess associations of atypical AD with mortality, Cox proportional hazard models were constructed including age, sex, education, MMSE score, and ε carriership (model 1), followed by adding the atypical AD group (model 2) or atypical AD variants (model 3). A likelihood ratio test was performed to compare the fit of model 1 and model 2.
A total of 2,081 patients (aged 65 ± 8 years, 52% female) were classified as typical AD (n = 1,801) or atypical AD (n = 280; PCA [n = 112], lvPPA [n = 86], and bvAD [n = 82]). The estimated median survival time for atypical AD of 6.3 years (95% CI [5.8-6.9]) was shorter than for typical AD (7.2 [7.0-7.5], = 0.02). Median survival durations across the atypical AD variants were consistently, albeit nonsignificantly, shorter (PCA: 6.3 [5.5-7.3], = 0.055; lvPPA: 6.6 [5.7-7.7], = 0.110; bvAD: 6.3 [5.0-9.1], = 0.121, 48% deceased). Including atypical AD improved the model fit (model 2; χ = 8.88, = 0.003) and was associated with 31% increased mortality risk compared with typical AD (hazard ratio [HR] = 1.31 [1.10-1.56], = 0.002). In model 3, contributions of the variants were as follows: HR = 1.35 (1.05-1.73), = 0.019; HR = 1.27 (0.94-1.69), = 0.114; HR = 1.31 (0.94-1.83), = 0.105.
Survival in atypical AD (PCA, lvPPA, bvAD) was shorter compared with typical AD. These atypical variants are associated with increased mortality beyond age, sex, education, ε carriership, and disease severity. Future studies are required to address generalizability of these findings and to identify factors that explain the observed survival differences.
阿尔茨海默病（AD）患者的生存估计有助于了解疾病轨迹，但关于非典型AD变异型的精确估计却很少。非典型AD变异型的特征为非遗忘型表型、发病早以及ε等位基因携带者患病率较低，这些因素会影响AD的病程。我们旨在提供后皮质萎缩（PCA）、语义变异型原发性进行性失语（lvPPA）和行为性AD（bvAD）的生存估计，并评估这些非典型AD诊断在已知死亡率决定因素之外的影响。
从阿姆斯特丹痴呆队列中，我们回顾性选择了在记忆门诊就诊且处于轻度认知障碍或痴呆阶段、生物标志物确诊的散发性AD患者。患者被分为非典型AD表型（PCA、lvPPA、bvAD；多学科共识及回顾性病例发现）和典型AD参照组（排除无法分类的非典型表现或未经证实的未来AD痴呆）。确定从首次就诊到死亡/截尾（中央公共管理部门）的生存估计（Kaplan-Meier分析），并在各诊断组间进行比较（对数秩检验）。为评估非典型AD与死亡率的关联，构建Cox比例风险模型，模型1纳入年龄、性别、教育程度、简易精神状态检查表（MMSE）评分和ε等位基因携带者情况，随后加入非典型AD组（模型2）或非典型AD变异型（模型3）。进行似然比检验以比较模型1和模型2的拟合优度。
总共2081例患者（年龄65±8岁，52%为女性）被分类为典型AD（n = 1801）或非典型AD（n = 280；PCA [n = 112]，lvPPA [n = 86]，bvAD [n = 82]）。非典型AD患者的估计中位生存时间为6.3年（95%置信区间[5.8 - 6.9]），短于典型AD患者（7.2 [7.0 - 7.5]，P = 0.02）。各非典型AD变异型的中位生存时间始终较短，尽管无统计学意义（PCA：6.3 [5.5 - 7.3]，P = 0.055；lvPPA：6.6 [5.7 - 7.7]，P = 0.110；bvAD：6.3 [5.0 - 9.1]，P = 0.121，48%死亡）。纳入非典型AD改善了模型拟合（模型2；χ² = 8.88，P = 0.003），与典型AD相比，死亡风险增加31%（风险比[HR] = 1.31 [1.10 - 1.56]，P = 0.002）。在模型3中，各变异型的贡献如下：HR = 1.35（1.05 - 1.73），P = 0.019；HR = 1.27（0.
