散发性早发阿尔茨海默病中磷酸化tau蛋白的高负荷和特异性楔前叶萎缩:一项前瞻性队列研究

High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer’s disease

早发性阿尔茨海默病(EOAD)是阿尔茨海默病(AD)的罕见且严重的亚型,于65岁之前发病,占所有AD病例的5%~10%.以往关于EOAD的研究主要集中在家族性遗传人群,而对于占EOAD病例85%~90%的散发性EOAD(sEOAD)的研究则较为有限.在这项前瞻性队列研究中,共纳入sEOAD110例,晚发性AD(LOAD)89例,年龄匹配对照组75例.研究对象排除了家族性EOAD患者,所有纳入AD患者均符合基于ATN框架下的生物标志物证据的诊断标准.对纳入患者进行了患病危险因素分析、多维度认知功能评估、多模态分子影像学评估及脑脊液/外周血生物标记物检测.结果显示,与LOAD患者相比,sEOAD患者没有表现出特定的危险因素,但表现出更严重的执行功能损害和双侧楔前叶萎缩.在sEOAD患者中的脑脊液和血浆中磷酸化tau181(P-tau181)水平较LOAD组显著升高.本研究探讨了散发性EOAD人群的临床特征,发现了tau蛋白磷酸化在sEOAD发生和进展中的重要性,有助于全面了解AD的病因、发病年龄决定因素和疾病进展,并为潜在的治疗策略提供了重要思路.

Early-onset Alzheimer’s disease(EOAD)is a rare devastating subclassification of Alzheimer’s disease(AD).EOAD affects individuals<65 years old,and accounts for 5%–10%of all AD cases.Previous studieson EOAD primarily focused on familial forms,whereas research on sporadic EOAD(sEOAD),which represents85%–90%of EOAD cases,is limited.In this prospective cohort study,participants were recruitedbetween 2018 and 2023 and included patients with sEOAD(n=110),late-onset AD(LOAD,n=89),youngcontrols(YC,n=50),and older controls(OC,n=25).All AD patients fulfilled the diagnostic criteria basedon biomarker evidence.Familial EOAD patients or non-AD dementia patients were excluded.Single moleculearray technology was used to measure fluid biomarkers,including cerebrospinal fluid(CSF)andplasma amyloid beta(Aβ)40,Aβ42,phosphorylated tau(P-tau)181,total tau(T-tau),serum neurofilamentlight chain and glial fibrillary acidic protein(GFAP).Patients with sEOAD exhibited more severeexecutive function impairment and bilateral precuneus atrophy(P<0.05,family-wise error corrected)than patients with LOAD.Patients with sEOAD showed elevated CSF and plasma P-tau181 levels(154.0±81.2 pg/mL,P=0.002;and 6.1±2.3 pg/mL,P=0.046).Moreover,precuneus atrophy was significantlycorrelated with serum GFAP levels in sEOAD(P<0.001).Serum GFAP levels(area under the curve(AUC)=96.0%,cutoff value=154.3 pg/mL)displayed excellent diagnostic value in distinguishing sEOADpatients from the control group.These preliminary findings highlight the crucial role of tau protein phosphorylationin the pathogenesis and progression of sEOAD.