Ogg Jordan, Postupna Nadia, Gibbons Laura E, Ariza Jeanelle, Xiao Ming, Fonseca Luciana M, Jayadev Suman, Keene C Dirk, Bird Thomas D, Latimer Caitlin S
Department of Laboratory Medicine and Pathology, University of Washington, 325 9th Ave, Seattle, WA, 98104, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
Acta Neuropathol. 2025 Sep 4;150(1):24. doi: 10.1007/s00401-025-02931-1.
Early onset familial Alzheimer's disease (EOFAD) is rare compared to sporadic AD, but dominant variants in genes involved in amyloid β (Aβ) processing are well-described. One such variant is in the presenilin 2 (PSEN2) gene, N141I, and was first described in a family with Volga German descent. Separately, individuals with Down syndrome (DS) are also at risk for early onset AD, having an extra copy of an amyloid precursor protein gene. While either can drive EOFAD alone, it is extremely rare for both to occur within one individual. Here we describe a unique case of a 48-year-old individual, with both DS and the PSEN2 N141I variant. We investigated whether having two high-risk AD variants results in worsened or distinct pathology compared to single variant carriers. Neuropathologic evaluation, quantitative pathology, and spatial proteomic profiling (NanoString Geomx Digital Spatial Profiling) were performed on post-mortem tissue of the index case compared to individuals with DS and N141I variants alone. Analysis in the index case revealed increased total Aβ burden in multiple brain regions compared to the average levels observed in PSEN2 carriers and DS cases, but not for hyperphosphorylated tau or neuroinflammatory markers. Index case appeared to have more pronounced Aβ pathological burden than the PSEN2 subgroup and was more similar to the DS subgroup in several measurements: the Aβ burden, density of Aβ plaques, fibrillar and dense-core plaques, and the density of ionized calcium binding adaptor molecule 1 (Iba1) labelling in MSTG. As such, it appears that compounded genetic risk for AD was additive for Aβ burden, but not tau or neuroinflammation. This rare case offers new insight into how compounded risk may additively enhance amyloid pathology independently from tau. This underscores the importance of investigating synergistic and additive risk in neurodegenerative disease.
与散发性阿尔茨海默病（AD）相比，早发型家族性阿尔茨海默病（EOFAD）较为罕见，但参与淀粉样β（Aβ）加工的基因中的显性变异已得到充分描述。其中一种变异存在于早老素2（PSEN2）基因中，即N141I，它最早在一个有伏尔加德意志血统的家族中被描述。另外，唐氏综合征（DS）患者也有早发型AD的风险，因为他们多了一份淀粉样前体蛋白基因。虽然这两种情况都可能单独引发EOFAD，但在同一个体中同时出现极为罕见。在此，我们描述了一例独特的病例，一名48岁个体同时患有DS和PSEN2 N141I变异。我们研究了与单变异携带者相比，拥有两种高风险AD变异是否会导致更严重或不同的病理变化。对该索引病例的尸检组织与单独患有DS和N141I变异的个体进行了神经病理学评估、定量病理学分析和空间蛋白质组学分析（NanoString Geomx数字空间分析）。对索引病例的分析显示，与PSEN2携带者和DS病例中观察到的平均水平相比，多个脑区的总Aβ负担增加，但磷酸化tau或神经炎症标志物未见增加。索引病例的Aβ病理负担似乎比PSEN2亚组更明显，在一些测量中与DS亚组更相似：Aβ负担、Aβ斑块密度、纤维状和致密核心斑块，以及中颞颞回沟（MSTG）中离子钙结合衔接分子1（Iba1）标记的密度。因此，AD的复合遗传风险似乎对Aβ负担具有累加作用，但对tau或神经炎症则不然。这个罕见病例为复合风险如何独立于tau累加增强淀粉样病理变化提供了新的见解。这突出了研究神经退行性疾病中协同和累加风险的重要性。
