AbstractINTRODUCTIONChanges in sleep physiology can predate cognitive symptoms by decades in persons with Alzheimer's disease (AD), but it remains unclear which sleep characteristics predict cognitive and neurodegenerative changes after AD onset.METHODSUsing data from a prospective cohort of mild to moderate AD (n = 60), we analyzed non‐rapid eye movement sleep spindles and slow oscillations (SOs) at baseline and their associations with baseline amyloid beta (Aβ) and tau and with cognition from baseline to 3‐year follow‐up.RESULTSHigher spindle and SO activity predicted significant changes in Aβ and tau at baseline, lower Alzheimer's Disease Assessment Scale Cognitive Subscale (better cognitive performance) score, and higher Mini‐Mental State Examination score from baseline to 36 months. Spindles and SOs mediated the effect of phosphorylated tau 181 (pTau181)/Aβ42 on cognition, while pTau181/aβ42 moderated the effect of spindles and SOs on cognition.DISCUSSIONOur findings demonstrate that spindle and SO activity during sleep constitute predictive and non‐invasive biomarkers of neurodegeneration and cognition in AD patients.Highlights Sleep spindles predict long‐term cognitive performance in AD. Sleep spindle and SOs can be predictive, non‐invasive biomarkers for AD. Sleep may be one of the most important modifiable risk factors for AD progression. Sleep microarchitecture is a novel therapeutic target for preserving brain heath. Sleep physiology can provide novel therapeutic targets to slow AD progression.