Pathophysiology of Agitation in AD

These changes may contribute to increased levels of aggression or agitation by interfering with brain areas responsible for thinking, planning, sensorimotor integration, and processing of environmental and social stimuli.^1,4 

These changes also impact multiple neurotransmitters, including serotonin, dopamine, and noradrenaline.⁵

Serotonergic deficiency. Reductions in 5-HT (serotonin) have been associated with hostility, impulsivity, and aggression in other neuropsychiatric patient populations.⁵

Dopamine. The relative preservation of dopaminergic function in the context of diminished cholinergic activity could underlie psychotic symptoms in AD, while such preservation in the context of diminished serotonergic activity in certain brain regions has been linked to aggressive or impulsive behaviors.⁵

Noradrenaline. The central noradrenergic system regulates arousal and autonomic function. There is some evidence implicating  hyperactivity of this system in agitation and aggressive behaviors in patients with AD.⁵

Neuropeptide Y. Neuropeptide Y (NPY), a neurotransmitter believed to play a role in anxiety, reduces noradrenergic activity. Therefore, low NPY could enhance the noradrenergic contribution to agitation.⁵

Neuroinflammation in the medial temporal region and its neighboring area is also associated with the development of agitation symptoms in patients with AD.⁶

Defining agitation in Alzheimer’s disease

The most common features of agitation in Alzheimer’s disease are restlessness, nervousness, irritability, and a persistent sense of unease.^7–9 Cohen-Mansfield and Billig proposed a definition of agitation in 1986 that Cohen-Mansfield expanded in 2008 as “inappropriate verbal, vocal, or motor activity not judged by an outside observer to result directly from perceptible needs or confusion of the agitated individual.”^10,11

Symptoms of agitation may manifest with abnormal motor behaviors, including pacing, as well as inappropriate verbal, vocal, or motor activity. Socially inappropriate disinhibition, wandering, and repetitive motor movements may also be present.^7-9

Specific categories of agitation, which include physical and verbal nonaggressive as well as aggressive features.¹² The severity of symptoms varies by the disruptiveness, type, and frequency of behavior.