<p>Slow wave activity, the signature of deep/slow wave sleep, has consistently been linked to amyloid-beta (Aβ), a biomarker of neurodegeneration. Less is known about how Aβ relates to specific microstructural processes within slow wave sleep, such as the coupling of slow waves and spindles, where better functioning reflects younger age, increased memory, and less brain atrophy. Here, we pooled and re-analyzed data from three clinical trials where participants underwent an adaptation night, a baseline night and a three-night acoustic stimulation intervention to boost slow wave activity. The baseline analysis included 47 older adults (age_mean = 70.5 (0.68)) with varying cognitive functioning, whereas the intervention analysis was conducted on a subsample of 39 older adults (age_mean = 70.5 (0.74)) with varying cognitive functioning. Blood samples post-baseline and post-intervention were analyzed for Aβ 1–42/1-40-ratio. Irrespective of cognitive functioning, slow wave–spindle coupling was the best predictor for baseline Aβ, better than slow wave activity, age or cognitive functioning. Specifically, better Aβ-levels were linked to a coupling physiology resembling a younger brain. While intervention-induced increases in slow wave activity were linked to a beneficial Aβ-response across all cognitive levels, increases in slow wave–spindle coupling benefited Aβ-response exclusively in cognitively impaired individuals. Our results suggest a link between SW–spindle coupling and Aβ going beyond slow wave activity. This hints towards a potential specific function of SW–spindle coupling related to the early pathophysiology of Alzheimer’s disease.</p>