Morbidity and medication use preceding a diagnosis of late-onset Alzheimer’s disease: a Danish nationwide study

INTRODUCTION: Symptoms of Alzheimer's disease can emerge years before diagnosis, but detailed temporal mapping of morbidity and medication use in the prodromal period is lacking. METHODS: We conducted a nationwide retrospective, incidence density-matched nested case-control study including individuals diagnosed with late-onset Alzheimer's disease in Danish memory clinics from 2016 to 2022 and cognitively healthy matched controls. Exposures were primary and secondary discharge diagnoses from hospital contacts, and redeemed prescriptions. RESULTS: A total of 19,102 patients and 57,306 matched controls were included. At 10 years before diagnosis, individuals who later developed late-onset Alzheimer's disease had more mental health and behavioral diagnoses and increased use of psychopharmaceuticals, as well as more injuries and hospital contacts for non-specific symptoms. During the five years and one-year preceding diagnosis, morbidity increased across multiple diagnostic categories, while most medication categories decreased. CONCLUSION: Our findings suggest that prodromal late-onset Alzheimer's disease is characterized by gradual accumulation of morbidity, with injuries and neuropsychiatric symptoms as the most persistent. This knowledge can guide future hypothesis-driven studies towards better characterization of the prodromal phase that may improve early detection, reduce the burden of unexplained symptoms experienced by patients and their caregivers, and support clinicians facing diagnostic uncertainty.