Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing

Noradrenergic and cholinergic systems are among the most vulnerable brain systems in neuropsychiatric diseases of ageing, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, and progressive supranuclear palsy. As these systems fail, they contribute directly to many of the characteristic cognitive and psychiatric symptoms. However, their contribution to symptoms is not sufficiently understood, and pharmacological interventions targeting noradrenergic and cholinergic systems have met with mixed success. Part of the challenge is the complex neurobiology of these systems, operating across multiple timescales, and with non-linear changes across the adult lifespan and disease course. We address these challenges in a detailed review of the noradrenergic and cholinergic systems, outlining their roles in cognition and behaviour, and how they influence neuropsychiatric symptoms in disease. By bridging across levels of analysis, we highlight opportunities for improving drug therapies and for pursuing personalised medicine strategies.