A data-driven study of Alzheimer's disease related amyloid and tau pathology progression.
A data-driven study of Alzheimer's disease related amyloid and tau pathology progression.
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DOI：
10.1093/brain/awad232
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发表时间：
2023-12-01
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影响因子：
--
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淀粉样蛋白-β被认为有助于tau蛋白在阿尔茨海默病的新皮层中的扩散，尽管这是如何发生的还不清楚。这是因为淀粉样蛋白-β和tau之间的空间不一致性，淀粉样蛋白-β在新皮质中积累，tau在老化过程中积累在内侧颞叶中。有证据表明，在某些情况下，淀粉样蛋白-β-非依赖性tau扩散到内侧颞叶之外，在内侧颞叶中它可能与新皮质淀粉样蛋白-β相互作用。这表明可能存在多种不同的阿尔茨海默病相关蛋白聚集的时空亚型，具有潜在的不同人口统计学和遗传风险特征。我们研究了这一假设，将数据驱动的疾病进展亚型模型应用于尸检神经病理学和两项大型观察性研究的体内PET测量：阿尔茨海默病神经影像学倡议（ADNI）和宗教秩序研究和拉什记忆和衰老项目（ROSMAP）。我们始终确定了“淀粉样蛋白第一”和“tau蛋白第一”的亚型使用的横截面信息，从两项研究。在淀粉样蛋白优先亚型中，广泛的新皮质淀粉样蛋白-β先于tau扩散到内侧颞叶之外，而在tau优先亚型中，轻度tau在与淀粉样蛋白-β相互作用之前在内侧颞叶和新皮质区域中积累。正如预期的那样，我们发现载脂蛋白E（APOE）ε4等位基因携带者中淀粉样蛋白第一亚型的患病率较高，而tau第一亚型在APOE ε4非携带者中更常见。在tau-第一APOE ε4携带者中，我们发现淀粉样蛋白-β积累的速率增加（通过纵向淀粉样蛋白PET），这表明这种罕见的群体可能属于阿尔茨海默病连续体。我们还发现，tau-第一APOE ε4携带者的受教育年限比其他群体少，这表明可改变的风险因素在促进淀粉样蛋白-β-非依赖性tau蛋白中的作用。相比之下，Tau-第一APOE ε4非携带者概括了原发性年龄相关性Tau病的许多特征。该组中纵向淀粉样蛋白-β和tau积累的速率（均通过PET测量）与正常衰老没有差异，支持原发性年龄相关性tau蛋白病与阿尔茨海默病的区别。我们还发现tau-first APOE ε4非携带者中纵向亚型一致性降低，表明该组中存在额外的异质性。我们的研究结果支持这样的观点，即淀粉样蛋白-β和tau蛋白可能开始作为空间上不连通的区域中的独立过程，广泛的新皮质tau蛋白是淀粉样蛋白-β和tau蛋白的局部相互作用的结果。这种相互作用的位点可能是亚型依赖性的：淀粉样蛋白首先位于内侧颞叶，tau蛋白首先位于新皮质。这些对淀粉样蛋白-β和tau的动力学的见解可以为针对这些病理学的研究和临床试验提供信息。Aksman等人使用数据驱动的亚型对阿尔茨海默病病理学的传播进行建模，识别淀粉样蛋白优先和tau优先亚型。β淀粉样蛋白和tau蛋白可能开始作为空间上不连通区域的独立过程，β淀粉样蛋白和轻度tau蛋白的局部相互作用触发广泛的新皮质tau蛋白。
Amyloid-β is thought to facilitate the spread of tau throughout the neocortex in Alzheimer's disease, though how this occurs is not well understood. This is because of the spatial discordance between amyloid-β, which accumulates in the neocortex, and tau, which accumulates in the medial temporal lobe during ageing. There is evidence that in some cases amyloid-β-independent tau spreads beyond the medial temporal lobe where it may interact with neocortical amyloid-β. This suggests that there may be multiple distinct spatiotemporal subtypes of Alzheimer's-related protein aggregation, with potentially different demographic and genetic risk profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post-mortem neuropathology and in vivo PET-based measures from two large observational studies: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). We consistently identified ‘amyloid-first’ and ‘tau-first’ subtypes using cross-sectional information from both studies. In the amyloid-first subtype, extensive neocortical amyloid-β precedes the spread of tau beyond the medial temporal lobe, while in the tau-first subtype, mild tau accumulates in medial temporal and neocortical areas prior to interacting with amyloid-β. As expected, we found a higher prevalence of the amyloid-first subtype among apolipoprotein E (APOE) ε4 allele carriers while the tau-first subtype was more common among APOE ε4 non-carriers. Within tau-first APOE ε4 carriers, we found an increased rate of amyloid-β accumulation (via longitudinal amyloid PET), suggesting that this rare group may belong within the Alzheimer's disease continuum. We also found that tau-first APOE ε4 carriers had several fewer years of education than other groups, suggesting a role for modifiable risk factors in facilitating amyloid-β-independent tau. Tau-first APOE ε4 non-carriers, in contrast, recapitulated many of the features of primary age-related tauopathy. The rate of longitudinal amyloid-β and tau accumulation (both measured via PET) within this group did not differ from normal ageing, supporting the distinction of primary age-related tauopathy from Alzheimer's disease. We also found reduced longitudinal subtype consistency within tau-first APOE ε4 non-carriers, suggesting additional heterogeneity within this group. Our findings support the idea that amyloid-β and tau may begin as independent processes in spatially disconnected regions, with widespread neocortical tau resulting from the local interaction of amyloid-β and tau. The site of this interaction may be subtype-dependent: medial temporal lobe in amyloid-first, neocortex in tau-first. These insights into the dynamics of amyloid-β and tau may inform research and clinical trials that target these pathologies. Aksman et al. model the spread of Alzheimer's disease pathologies using data-driven subtyping, identifying amyloid-first and tau-first subtypes. Amyloid-beta and tau may begin as independent processes in spatially disconnected regions, with local interaction of amyloid-beta and mild tau triggering widespread neocortical tau.
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影响因子：
3.2
作者：
Crane, Paul K.;Carle, Adam;Gibbons, Laura E.;Insel, Philip;Mackin, R. Scott;Gross, Alden;Jones, Richard N.;Mukherjee, Shubhabrata;Curtis, S. McKay;Harvey, Danielle;Weiner, Michael;Mungas, Dan
通讯作者：
Mungas, Dan
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
基因相同的双胞胎表现出相似的 tau PET 负载和空间分布。
DOI：
10.1093/brain/awac004
发表时间：
2022-10-21
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.2
作者：
Gibbons, Laura E.;Carle, Adam C.;Mackin, R. Scott;Harvey, Danielle;Mukherjee, Shubhabrata;Insel, Philip;Curtis, S. McKay;Mungas, Dan;Crane, Paul K.
通讯作者：
Crane, Paul K.