Hypothalamic structural differences link sleep and cognition across the Alzheimer’s disease spectrum

ABSTRACT INTRODUCTION Sleep disturbance is common across the Alzheimer’s disease (AD) spectrum, yet the structural substrates linking sleep disruption and cognitive decline remain unclear. The hypothalamus regulates sleep–wake function and is affected by AD pathology, but its role across clinical stages is poorly defined. METHODS 672 older adults classified as subjective cognitive decline, single- and multi-domain mild cognitive impairment, or probable AD underwent structural MRI. Subjective insomnia measures were available for the full cohort, and 209 underwent polysomnography. Associations between hypothalamic volume, sleep architecture, and cognition were examined. RESULTS Hypothalamic volume declined progressively from SCD to MD-MCI and AD, with the greatest reductions in anterior subregions. Smaller hypothalamic volume associated with diminished slow-wave sleep, lower REM sleep in SD-MCI, poorer neuropsychological functions, and moderated the association between hippocampal volume and memory. CONCLUSION Hypothalamic atrophy emerges along the AD continuum, and relates to specific alterations in sleep quality and cognition.