BrainAge moderates associations between Alzheimer's disease biomarkers and cognitive decline: a meta-analysis across A4/LEARN, HABS and ADNI cohorts

BrainAge delta, the difference between a persons predicted brain age and their chronological age, is a promising marker of the accumulation of neurodegeneration that may increase vulnerability to Alzheimers disease (AD). In this study we use structural MRI regions vulnerable to AD, the hippocampus, the amygdala and cortical thickness measurements to build BrainAge models. We examined whether BrainAge delta moderates the relationship between AD biomarkers and longitudinal cognitive decline performing a meta-analysis across three cohorts: A4/LEARN, HABS and ADNI (2,279 cognitively unimpaired [CU]; 416 with mild cognitive impairment [MCI]). Higher BrainAge delta was linked to faster decline in CU ({beta} = -0.13 [-0.21, - 0.06], p = 0.018, I2=1%) and more strongly in MCI ({beta} = -0.31 [-0.30, -0.24], p < 1x10-16). BrainAge also interacted with A{beta}-PET ({beta} = -0.09 [-0.13, -0.05], p = 0.0054, I2=12%) and plasma pTau217 ({beta} = -0.09 [-0.15, -0.03], p = 0.018, I2=0.1%), but not Tau-PET, to impact cognitive decline, where synergistically higher BrainAge delta and elevated AD markers resulted in faster cognitive decline. We next tested its utility for clinical trial enrichment. Sequential screening with pTau217 and BrainAge delta reduced required sample size for prevention trials by 77%, versus 61% using pTau217 alone. These findings support BrainAge delta as a marker of neurodegeneration and may serve as an enrichment tool for AD prevention trials.