Early-onset (age < 65) Alzheimer’s disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration, and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer’s disease who underwent neurological evaluation, neuropsychological testing, 11C- Pittsburgh Compound B PET (amyloid-PET), and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function, and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores, and early-onset versus late-onset differences were tested with a PET*age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions-of-interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal, and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C- Pittsburgh Compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C- Pittsburgh Compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g., left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer’s disease and in the total sample, and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer’s disease. Tau had an association with cognition independent of neurodegeneration in language, executive, and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer’s disease across the broad spectrum of ages and clinical phenotypes in Alzheimer’s disease.

中文翻译：

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淀粉样蛋白、tau 蛋白和代谢 PET 与早发型和晚发型阿尔茨海默病的认知相关


与晚发性疾病相比，早发性（年龄 < 65）阿尔茨海默病与更大的非遗忘性认知症状和神经病理学负担相关。目前尚不完全清楚这些群体在分子病理学、神经退行性变和认知表现之间的关联方面是否也存在差异。我们研究了早发淀粉样蛋白阳性患者（n = 60，平均年龄 58 ± 4，MMSE 21 ± 6，58% 女性）和晚发淀粉样蛋白阳性患者（n = 53，平均年龄 74 ± 6，MMSE 23 ± 5， 45% 女性）阿尔茨海默病患者接受了神经学评估、神经心理学测试、11C-匹兹堡化合物 B PET（淀粉样蛋白-PET）和 18F-弗洛托西吡酯 PET（tau-PET）。 74% (n = 84) 的参与者也可以使用 18F-氟脱氧葡萄糖 PET（脑葡萄糖代谢 PET）。基于认知未受损的对照，计算情景记忆、语义记忆、语言、执行功能和视觉空间领域的综合分数。体素回归评估了 PET 生物标志物与认知评分之间的相关性，并通过 PET* 年龄组交互作用测试了早发型与迟发型差异。中介分析估计了 ​​18F-flortaucipir 结合与特定领域感兴趣区域认知评分之间的直接和间接（18F-氟脱氧葡萄糖介导）局部关联。我们发现，早发型患者在顶叶、外侧颞叶和外侧额叶皮质中具有较高的 18F-flortaucipir 结合力；楔前叶和角回更严重的 18F-氟脱氧葡萄糖代谢减退；与晚发患者相比，枕叶区域的 11C-匹兹堡化合物 B 结合更强。在我们的初步分析中，PET 认知相关性在不同年龄组之间没有显着差异。18F-弗洛托西吡和 18F-氟脱氧葡萄糖，但不是 11C-匹兹堡化合物 B，与两个年龄组的预期特定领域模式的认知显着相关（例如，左侧裂/语言、额叶/执行、枕叶/视觉空间）。 18F-氟脱氧葡萄糖在两个年龄组中介导 18F-flortaucipir 与认知之间的关系，涉及所有领域（晚发患者的情景记忆除外）。观察到 18F-flortaucipir 对所有年龄组的执行功能、早发性阿尔茨海默病和总样本中的语言以及总样本中的视觉空间功能的其他直接影响。总之，tau 蛋白和神经退行性疾病（而非淀粉样蛋白）与早发性和晚发性阿尔茨海默病的认知具有相似的相关性。在总样本中，Tau 蛋白与认知相关，独立于语言、执行和视觉空间功能的神经退行性变。我们的研究结果支持 tau PET 作为一种生物标志物，可以捕获阿尔茨海默病的临床严重程度和特定于阿尔茨海默病的广泛年龄和临床表型的分子病理学。