Garcia Condado Jorge, Klinger Hannah M, Birkenbihl Colin, Cuppels Madison, Liu Annie, Tellaetxe Elorriaga Iñigo, Seto Mabel, Couglan Gillian T, Properzi Michael J, Rentz Dorene M, Schultz Aaron P, Erramuzpe Asier, Yang Hyun-Sik, Chhatwal Jasmeer, Johnson Keith A, Healy Brian C, Cortes Jesus M, Sperling Reisa A, Donohue Michael, Hohman Timothy J, Diez Ibai, Buckley Rachel F
Computational Neuroimaging Lab, BioBizkaia Health Research Institute, Barakaldo, Spain.
Biomedical Research Doctorate Program, Universidad del Pais Vasco (UPV/EHU), Leioa, Spain.
medRxiv. 2025 Jul 10:2025.07.07.25331026. doi: 10.1101/2025.07.07.25331026.
BrainAge delta, the difference between a person's predicted brain age and their chronological age, is a promising marker of the accumulation of neurodegeneration that may increase vulnerability to Alzheimer's disease (AD). We examined whether BrainAge delta moderates the relationship between AD biomarkers and longitudinal cognitive decline performing a meta-analysis across three cohorts (2,279 cognitively unimpaired [CU]; 416 with mild cognitive impairment [MCI]). Higher BrainAge delta was linked to faster decline in CU (β = -0.13 [-0.21, -0.06], p = 0.018, I=1%, =0.00) and more strongly in MCI (β = -0.31 [-0.30, -0.24], p < 1×10). BrainAge also interacted with Aβ-PET (β = -0.09 [-0.15, -0.05], p = 0.0054, I =12%, =0.00) and plasma pTau (β = -0.09 [-0.15, -0.03], p = 0.018, I=8%, =0.00), but not Tau-PET, to impact cognitive decline. We next tested its utility for clinical trial enrichment. Sequential screening with pTau and BrainAge delta reduced required sample size for prevention trials by 76%, versus 59% using pTau alone. These findings support BrainAge delta as a marker of neurodegeneration and may serve as an enrichment tool for AD prevention trials.
脑龄差值，即一个人的预测脑龄与实际年龄之间的差异，是神经退行性变积累的一个有前景的标志物，这种积累可能会增加患阿尔茨海默病（AD）的易感性。我们通过对三个队列（2279名认知未受损者[CU]；416名轻度认知障碍者[MCI]）进行荟萃分析，研究了脑龄差值是否会调节AD生物标志物与纵向认知衰退之间的关系。较高的脑龄差值与CU组中更快的认知衰退相关（β = -0.13[-0.21, -0.06]，p = 0.018，I = 1%，Q = 0.00），在MCI组中相关性更强（β = -0.31[-0.30, -0.24]，p < 1×10⁻⁴）。脑龄还与淀粉样蛋白正电子发射断层扫描（Aβ-PET）（β = -0.09[-0.15, -0.05]，p = 0.0054，I = 12%，Q = 0.00）和血浆磷酸化tau蛋白（pTau）（β = -0.09[-0.15, -0.03]，p = 0.018，I = 8%，Q = 0.00）相互作用，但与Tau-PET不相互作用，从而影响认知衰退。接下来，我们测试了它在临床试验富集方面的效用。与单独使用pTau相比，使用pTau和脑龄差值进行序贯筛查可将预防试验所需的样本量减少7₆%，而单独使用pTau时减少59%。这些发现支持脑龄差值作为神经退行性变的标志物，并可能作为AD预防试验的富集工具。
