SLEEP MEDICATION USE AND RISK OF PARKINSON’S DISEASE AND ALZHEIMER’S DISEASE SUBTYPE-SPECIFIC ASSOCIATIONS IN A NESTED CASE-CONTROL STUDY

Sleep disturbance is closely linked to neurodegeneration, and sleep medications are widely prescribed for insomnia. Experimental studies suggest that certain hypnotic agents may influence sleep-related neurophysiological processes, including pathways involved in brain metabolite clearance, raising the possibility that pharmacologic modulation of sleep may differentially affect neurodegenerative disease risk. However, whether such associations vary by disease subtype or medication class remains unclear.
We conducted a nationwide nested case–control study using a Japanese health insurance claims database from 2005 to 2025. Incident cases of neurodegenerative disease (Parkinson’s disease or Alzheimer’s disease) were identified and matched to controls by age, sex, and duration of insurance enrollment. Sleep medication use was ascertained from outpatient prescription claims, excluding prescriptions within two years before diagnosis to minimize reverse causation. Medications were classified as benzodiazepines and Z-drugs, orexin receptor antagonists, or melatonin receptor agonists. Associations were assessed using multivariable conditional logistic regression.
Sleep medication use was observed more frequently among cases than controls and was associated with an increased risk of incident neurodegenerative disease. Associations varied by disease subtype, with larger associations observed for Parkinson’s disease than for Alzheimer’s disease. In analyses by pharmacologic class of sleep medications, associations for benzodiazepines and Z-drugs were higher than those for orexin receptor antagonists and melatonin receptor agonists, particularly for Parkinson’s disease.
These findings indicate disease-specific heterogeneity in the association between sleep medication use and neurodegeneration, suggesting that sleep-related pharmacologic modulation may be differentially associated with neurodegenerative processes across disease subtypes.