Freudenberg-Hua Yun, Giliberto Luca, D'Abramo Cristina, Li Wentian, Ma Yilong, Goate Alison, Koppel Jeremy
Center for Alzheimer's Disease Research, Institute of Molecular Medicine, the Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
Division of Geriatric Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY.
medRxiv. 2025 Feb 25:2025.02.24.25322783. doi: 10.1101/2025.02.24.25322783.
Plasma levels of protein biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers, but it is unclear how risk genes for Alzheimer's disease (AD) influence levels of these biomarkers. We investigated the association of the established high-effect variants for AD in and with these biomarkers, using data from over 50,000 participants from the UK Biobank (UKB). The results show that is associated with elevated levels of plasma GFAP, and to a lesser extent, NEFL. The effect on GFAP increases with age and the number of alleles. The risk variants R47H and R62H in are associated with higher NEFL levels, but not with GFAP, and the effect sizes do not increase with age. Higher levels of both GFAP and NEFL in midlife are significantly associated with greater risk for incident dementia. In contrast, the protective allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for AD differentially affect dementia protein biomarkers across age, indicating gene specific pathways with potential therapeutic implications.
血浆中胶质纤维酸性蛋白（GFAP）和神经丝轻链（NEFL）等蛋白质生物标志物水平是关键的痴呆生物标志物，但尚不清楚阿尔茨海默病（AD）的风险基因如何影响这些生物标志物的水平。我们利用来自英国生物银行（UKB）50000多名参与者的数据，研究了已确定的AD高效应变体与这些生物标志物之间的关联。结果表明，[此处原文缺失相关基因名称]与血浆GFAP水平升高有关，在较小程度上与NEFL水平升高有关。[此处原文缺失相关基因名称]对GFAP的影响随年龄和[此处原文缺失相关基因名称]等位基因数量的增加而增加。[此处原文缺失相关基因名称]中的风险变体R47H和R62H与较高的NEFL水平相关，但与GFAP无关，且效应大小不随年龄增加。中年时较高的GFAP和NEFL水平均与痴呆发病风险增加显著相关。相比之下，保护性[此处原文缺失相关基因名称]等位基因对GFAP或NEFL没有影响。总之，我们发现AD的主要遗传风险因素在不同年龄对痴呆蛋白质生物标志物有不同影响，表明具有潜在治疗意义的基因特异性途径。
