AbstractBackgroundAcross the healthy adult lifespan, our brain’s undergo widespread structural change. Many of these changes – occurring gradually across life – are not qualitatively distinct from atrophy patterns seen in Alzheimer’s disease (AD), raising the possibility accelerated longitudinal brain change across healthy adult life may relate to genetic AD‐risk.MethodWe modelled subject‐specific structural brain change relative to that expected given age, in dense longitudinal adult lifespan data (1430 scans from 420 individuals aged 30 to 89 years; 2‐7 timepoints). Using polygenic AD scores (PRS‐AD) from four GWAS, we tested PRS‐AD associations with age‐relative change in early Braak stage regions – namely hippocampus, entorhinal cortex, amygdala, and medial temporal cortex. Next, to empirically identify features with accelerated change in AD, in ADNI data (scans = 4410; N = 978) we applied machine learning classification on the subject‐specific slopes estimated from individuals classed as consistently healthy over time versus those succumbing to AD. In healthy adult lifespan data, we then tested PRS‐AD associations with age‐relative change, in many combinations of brain features with model‐implied importance. Lastly, we tested whether high PRS‐AD individuals showing more negative brain change exhibit more longitudinal memory decline over healthy adult life.ResultIn healthy adult lifespan data, we observed many significant PRS‐AD associations with age‐relative change in hippocampus (bilateral), right entorhinal cortex, amygdala (bilateral), and left medial temporal cortex, and typically for all four scores (FDR‐corrected). We show that age‐relative change across the healthy adult lifespan in many combinations of AD‐accelerated features is significantly associated with PRS‐AD. As proof‐of‐principle, applying the ADNI‐derived model weights to the healthy adult lifespan data also enabled detection of PRS‐AD associations in healthy adults, but only using models trained on age‐relative change. Most, but not all, of the observed PRS‐AD associations were driven by APOE. Finally, we find high PRS‐AD individuals with more negative brain change exhibit significantly more memory decline, relative to high PRS‐AD individuals with less brain change.ConclusionThe results support a dimensional account linking gradual lifespan brain changes with pathological aging, and demonstrate PRS‐AD impacts the slope of brain aging in most AD‐relevant brain regions in healthy adults.