To report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).

Four copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription–digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.

Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.

Increased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.

报告淀粉样蛋白-β 前体蛋白 ( APP ) 基因座与相关信使 RNA (mRNA) 在常染色体显性早发性脑淀粉样血管病 (CAA) 和阿尔茨海默病 (AD) 家族中的三重表达。

通过短荧光片段的定量多重 PCR、荧光原位杂交 (FISH) 和阵列比较基因组杂交鉴定了APP基因的四个拷贝。在先证者的全血中使用逆转录-数字液滴 PCR 评估APP mRNA 水平，并与 10 名对照和 9 名APP重复携带者进行比较。

从 39 岁开始，先证者出现严重的情景记忆缺陷，其脑脊液生物标志物是 AD 的典型特征，脑 MRI 显示后部区域出现多发性脑叶微出血。他的父亲从 37 岁开始癫痫发作和反复脑出血。他的脑活检显示血管周围有大量淀粉样蛋白沉积物，导致诊断为 CAA。在先证者中，我们确定了位于染色体 21q21.3 上的 506-kb 区域的 4 个拷贝，包含整个APP基因，没有任何其他基因。FISH提示先证者基因型为3拷贝/1拷贝，对应APP基因座三倍，这与健康母亲存在2个APP拷贝和父亲病史一致。分析与对照组相比，APP mRNA 水平显示先证者增加 2 倍，APP重复携带者增加 1.8 倍。

APP拷贝数增加足以导致 AD 和 CAA，与重复相比，在三倍的情况下可能更早发病。