Sleep Disruption in Early‐Onset Alzheimer's Disease

Abstract Background Atypical variants of sporadic Alzheimer's disease (AD) are characterized by earlier onset (EOAD, before age 65), non‐amnestic cognitive patterns, and distinctive neuropsychiatric and sleep‐related traits. Earlier onset has been linked to greater severity of neuropsychiatric symptoms and increased use of antidepressants or sleep medications. Furthermore, atypical variants such as Posterior Cortical Atrophy and the logopenic variant of Primary Progressive Aphasia exhibit pronounced REM sleep dysfunction. The mechanisms driving these behavioral and sleep differences, influenced by age at onset and atypical disease features, remain unclear. Emerging evidence suggests that a differential pattern of degeneration within the neuromodulatory subcortical systems (NSS), including the locus coeruleus (LC), may contribute to these distinct profiles. This study compared sleep‐wake patterns and volumes of NSS in EOAD and late‐onset AD (LOAD). Method The study included 113 biomarker‐confirmed AD participants (37 EOAD, 76 LOAD) in the early stages (mild cognitive impairment or mild dementia). All participants underwent MRI with quantification of subcortical nucleus volumes. A subset of 66 participants (23 EOAD, 43 LOAD) completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and two weeks of actigraphy monitoring using the Motion Watch8 device. Sleep‐wake patterns and circadian rhythms were analyzed using MotionWare software. Result EOAD and LOAD participants had similar functional status (GDS3: 57% vs 55%), neuropsychiatric medication use (46% vs 42%), and subjective sleep assessments (PSQI: 6.55±4.33 vs 6.98±3.89; ESS: 6.45±4.35 vs 5.48±4.01). However, actigraphy revealed shorter total sleep time (384.07±67.06 vs. 425.00±58.09 min, p < 0.05) and more fragmented, unstable sleep patterns (384.13±68.57 vs. 419.33±57.17 min, p < 0.05) in EOAD compared to LOAD. Unlike other subcortical nuclei, LC volume was significantly smaller in EOAD than in LOAD (26.32±8.51 vs. 32.02±9.83 mm 3 ) (see Table 1). Conclusions While subjective sleep measures were similar between EOAD and LOAD, actigraphy revealed more significant sleep disruption in EOAD. Notably, LC volume was uniquely reduced in EOAD, whereas other subcortical nuclei showed larger volumes than LOAD. These findings highlight the need to explore the role of subcortical degeneration in sleep disturbances in early‐onset AD.