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 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, I²=1%, τ²=0.00) and more strongly in MCI (β = -0.31 [-0.30, -0.24], p < 1x10^-16). BrainAge also interacted with Aβ-PET (β = -0.09 [-0.15, -0.05], p = 0.0054, I²=12%, τ² = 0.00) and plasma pTau₂₁₇ (β = -0.09 [-0.15, -0.03], p = 0.018, I²=8%, τ² = 0.00), but not Tau-PET, to impact 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 76%, versus 59% using pTau₂₁₇ alone. These findings support BrainAge delta as a marker of neurodegeneration and may serve as an enrichment tool for AD prevention trials.