Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Alzheimers Dement. 2022 Dec;18(12):2458-2467. doi: 10.1002/alz.12567. Epub 2022 Feb 9.
Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.
We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers.
Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort.
GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.
颗粒体蛋白前体（GRN）突变可发生于额颞叶痴呆（FTLD）和阿尔茨海默病（AD）中，通常伴有 TDP-43 病理学改变。
我们在两个尸检队列和一个家系队列中，测定了 rs5848 及罕见致病性 GRN 突变的频率。我们比较了 GRN 携带者与非携带者的 Braak 分期、β-淀粉样蛋白负荷、磷酸化 tau（PHFtau）缠结密度和 TDP-43 病理学。
与基因组聚集数据库（gnomAD）相比，所有队列中的致病性 GRN 突变频率均较高，但与 AD 无关。在调整年龄、性别和 APOE ε4 基因型后，致病性 GRN 携带者的 PHFtau 缠结密度显著升高。rs5848 的 AD 患者的海马硬化和 TDP-43 沉积物的频率更高。在家系队列中观察到 22 种罕见的致病性 GRN 变体。
临床和神经病理学 AD 中的 GRN 突变增加了与 tau 相关的脑病理学负担，但与 β-淀粉样蛋白负荷或 AD 无特定关联。
