What Causes Agitation in Alzheimer’s Disease?

Agitation is one of the most common and distressing behavioral symptoms in Alzheimer’s disease, affecting a wide range of people across every stage of the illness. It can look like pacing, shouting, resisting care, or physical aggression, and it tends to worsen as cognitive decline advances. The underlying biology involves measurable brain changes, from shrinking of key regions to disrupted signaling between nerve cells, which means agitation is not simply a reaction to confusion or frustration. Understanding what drives it, how to recognize it early, and what actually helps are among the most pressing questions families and clinicians face.

What Agitation Looks Like and How It Is Defined

Agitation in Alzheimer’s is not a single behavior. It spans a range of actions grouped loosely into three categories: physically aggressive behavior (hitting, kicking, grabbing), physically nonaggressive behavior (pacing, wandering, restlessness, repetitive movements), and verbal agitation (yelling, cursing, making repeated demands). These behaviors become clinically significant when they are persistent, cause distress to the person or those around them, and cannot be fully explained by another psychiatric condition or an obvious physical cause like pain or infection.

The International Psychogeriatric Association (IPA) has formalized criteria specifically for agitation in cognitive disorders, and screening tools have been developed based on those criteria. One recent example, the Agitation in Alzheimer’s Screener for Caregivers (AASC), was built from expert input and interviews with caregivers, then tested for its ability to predict agitation as defined by IPA standards.¹ Tools like this matter because agitation is often underreported. Caregivers may dismiss early signs as part of “normal” dementia or feel uncertain about when restlessness crosses the line into a clinical problem.

How Common Agitation Is and How It Changes Over Time

Published estimates of agitation prevalence in dementia vary widely depending on the setting and how agitation is measured, but systematic reviews consistently show it is among the most frequent neuropsychiatric symptoms in Alzheimer’s.² In long-term care facilities, rates tend to be higher than in community-dwelling populations, partly because people with more severe symptoms are more likely to be placed in residential care.

Agitation does not remain static. Longitudinal research shows that the rate at which agitation and aggression increase is tied to how quickly a person’s cognition and independence decline.³ In other words, faster cognitive deterioration tends to bring faster escalation of agitated behavior. Several studies also point to a positive association between agitation and mortality, suggesting that agitation is not just a quality-of-life issue but a marker of worse overall prognosis.⁴

What Is Happening in the Brain

Agitation in Alzheimer’s is rooted in identifiable biological changes, not just environmental frustration. The current model points to a combination of chemical imbalances and structural brain damage. Noradrenergic hyperactivity, meaning too much activity in the brain’s “fight or flight” signaling system, appears to play a role alongside deficits in serotonin and dysregulated dopamine release in the striatum.⁵ In plainer terms, the brain’s calming signals weaken while its alarm signals become overactive.

On top of those chemical shifts, agitation correlates with physical shrinkage in specific brain regions. Imaging studies find that greater agitation severity is tied to greater atrophy of frontal, insular, amygdala, cingulate, and hippocampal areas.⁶ These are regions involved in emotional regulation, impulse control, and processing of social cues. When they atrophy, the brain loses its ability to modulate reactions to stress or discomfort. This pattern has been confirmed across multiple studies, including those finding decreased grey matter specifically in the left insula and the anterior cingulate cortex in agitated patients.⁷

There is also growing evidence that neuroinflammation drives agitation. PET imaging studies using specialized tracers show that agitation severity correlates with inflammation in the medial temporal region, including the amygdala, hippocampus, and surrounding structures.⁸ This suggests that the immune response inside the brain, already ramped up in Alzheimer’s, may be particularly intense in the areas governing emotional reactivity in people who develop agitation.

Pain, Sundowning, and Other Triggers Caregivers Should Know

Not all agitation stems from disease progression alone. Many episodes are triggered or worsened by unmet physical needs, and the most common overlooked cause is pain. People with advanced Alzheimer’s often cannot articulate that something hurts, so discomfort comes out as restlessness, verbal aggression, repetitive calling out, or pacing. Research shows that verbal agitation behaviors like complaining, cursing, and constant requests for attention, as well as restlessness and pacing, responded to pain treatment with analgesics.⁹ When a person with dementia suddenly becomes more agitated, pain assessment should be among the first steps, not an afterthought.

Sundowning, the tendency for agitation and confusion to spike in the late afternoon and evening, is another well-recognized pattern. Research indicates that Alzheimer’s disease itself disrupts circadian rhythms, and sundowning appears linked to a phase delay in body temperature regulation caused by the disease.¹⁰ The internal clock essentially drifts, so the body’s signals for wakefulness and rest become misaligned with the actual time of day. This helps explain why evenings can be so difficult, and why maintaining consistent light exposure and daily routines matters.

Other common triggers include hunger, thirst, constipation, urinary tract infections, overstimulating environments, sudden changes in routine, and caregiver approaches that feel confrontational. Because the person with dementia often cannot identify or communicate the source of their distress, detective work on the caregiver’s part is essential.

The Toll on Caregivers and the Path to Institutional Care

Agitation is not just hard on the person experiencing it. It is often the tipping point for families. Agitated behavior raises concerns about self-harm, harms to others, and a general deterioration in quality of life that places enormous strain on caregivers.¹¹ Across large datasets, people with Alzheimer’s who develop agitation are roughly a fifth more likely to be moved into institutional care compared with those who do not develop agitation.

The financial impact is also substantial. Real-world claims analyses show that total healthcare costs for people with agitation in Alzheimer’s run several thousand dollars per year higher than for those without agitation, driven primarily by more hospitalizations and more time in skilled nursing facilities.¹² Emergency department visits are also about a fifth more frequent in the agitation group.¹³ These numbers make agitation not just a clinical problem but a significant public-health and economic one.

Non-Drug Approaches as First-Line Treatment

Most clinical guidelines recommend trying non-pharmacological strategies before medications. The umbrella term for many of these strategies is person-centered care, which means tailoring activities, communication, and the environment to the individual’s history, preferences, and current abilities rather than applying a one-size-fits-all routine.

The evidence for person-centered care is real but uneven. One meta-analysis of randomized controlled trials found that person-centered approaches reduced agitation, with short-term individualized activity interventions showing the largest benefit.¹⁴ A study in Australian rural nursing homes also found significant declines in aggressive behavior, physically nonaggressive behavior, verbal agitation, and hiding-and-hoarding behaviors after implementing a person-centered intervention.¹⁵ However, a separate systematic review focused on residential aged care found that the pooled data did not reach statistical significance for reducing agitation.¹⁶ The mixed picture likely reflects how hard it is to standardize these interventions. The quality of person-centered care depends heavily on staff training, time, and consistency, factors that vary enormously across care settings.

Sensory-based interventions have their own evidence base. Individual music therapy has shown a medium-sized reduction in agitation disruptiveness compared with standard care in a randomized trial.¹⁷ Bright light therapy has shown limited direct evidence for reducing agitation but appears to improve sleep, which may indirectly help, and may be more effective in winter months when natural light is scarce.¹⁸ Broader reviews of sensory stimulation approaches, including aromatherapy, multisensory rooms, and rhythmic stimulation, suggest they can improve behavior and cognition in Alzheimer’s, though the quality of the evidence varies across modalities.¹⁹

Antipsychotics and Their Serious Risks

For decades, antipsychotic medications were the go-to pharmacological response to agitation in dementia, despite never being approved specifically for that purpose. They do reduce agitation in some people, but the tradeoff is grim. In people with dementia, antipsychotics carry a well-documented increase in the risk of death, which led to a boxed warning from regulators. Beyond mortality, a large matched cohort study found that current antipsychotic use in people with dementia was associated with roughly double the risk of pneumonia, along with meaningfully increased risks of acute kidney injury, blood clots, and stroke.²⁰ These risks are not theoretical edge cases; pneumonia and fracture had the highest incidence rates among the adverse outcomes tracked.

Updated reviews confirm the pattern: antipsychotics in older patients with dementia may increase mortality and are associated with pneumonia, cerebrovascular events, parkinsonian symptoms, and higher rates of blood clots.²¹ This is why guidelines now emphasize that antipsychotics should be reserved for severe agitation that poses an immediate safety risk and has not responded to other interventions, and even then used at the lowest dose for the shortest possible time.

Brexpiprazole and the Search for Safer Medication

In 2023, brexpiprazole became the first medication to receive FDA approval specifically for agitation associated with Alzheimer’s dementia. It is an atypical antipsychotic, but it differs from older drugs in its receptor profile and has been studied specifically in this population. In a pivotal randomized trial, patients taking brexpiprazole at higher doses showed significantly greater improvement on a standard agitation scale compared with placebo over twelve weeks, with a modest but statistically significant effect size.²² The side effect profile was relatively favorable: no single adverse event occurred in five percent or more of the brexpiprazole group at a rate exceeding placebo.

Earlier trials told a similar story. One prior study found that the two milligram daily dose significantly outperformed placebo on agitation measures, with the most common side effects being headache, insomnia, and dizziness, most of which were mild or moderate.²³ The approval was welcomed because it gave clinicians a tool with actual regulatory backing, though the effect size is modest and the drug does not work for everyone. Brexpiprazole is still an antipsychotic, and clinicians generally treat it as a step to try after non-drug interventions, not a first resort.

Citalopram and Mixed Signals From Antidepressants

Because serotonin deficits are implicated in agitation, researchers have explored whether antidepressants that boost serotonin might help. The most-studied example is citalopram, a common SSRI. A landmark randomized controlled trial (CitAD) found that citalopram at 30 milligrams daily significantly improved agitation compared with placebo, with about 40 percent of participants showing moderate or marked improvement versus 26 percent on placebo.²⁴ However, at that dose, citalopram also caused a small but clinically meaningful worsening of cognitive scores and raised concerns about cardiac effects, specifically QT prolongation.

When data from multiple trials of citalopram and the closely related escitalopram were pooled in a recent meta-analysis, the overall picture was less encouraging: the pooled analysis did not show significant improvement in agitation severity.²⁵ The discrepancy between the positive single trial and the neutral pooled result highlights how common it is for a single promising trial not to hold up once more data accumulate. SSRIs remain an option clinicians consider, especially when agitation has an anxious or depressive quality, but they are not reliably effective across the board.

Cannabinoids as an Emerging Option

Interest in cannabinoids for agitation in Alzheimer’s has grown because of their potential to reduce anxiety, ease inflammation, and improve sleep, all of which could address contributing factors. Preclinical work and early clinical evidence suggest cannabinoids may regulate neurotransmitters relevant to agitation and improve circadian rhythms.²⁶

A recent randomized controlled trial tested dronabinol (synthetic THC) against placebo for three weeks in people with Alzheimer’s and agitation. Dronabinol decreased agitation to a greater extent than placebo on one of two primary outcomes, reaching statistical significance with a moderate effect size.²⁷ On the second primary outcome, the difference did not reach significance. Earlier reviews of smaller studies with dronabinol and nabilone similarly showed benefits but were limited by small sample sizes and inconsistent study designs.²⁸ Cannabinoids remain experimental for this use, and larger, longer trials are needed before they can be recommended as a standard treatment. But the early results are promising enough to keep clinical researchers interested.

Genetic Clues to Who Develops Agitation

Not everyone with Alzheimer’s develops agitation, and researchers are working to understand why some people are more vulnerable. Systematic reviews have identified several classes of biological markers linked to agitation, including genetic variations, neurotransmitter profiles, brain imaging patterns, inflammatory markers, and the apolipoprotein E (APOE) genotype that is already well known as a risk factor for Alzheimer’s itself.²⁹

One specific genetic finding stands out. A variation in the serotonin 2A receptor gene has been significantly associated with agitation and aggression scores. Patients who carry one or two copies of a particular form of this gene (the 102T polymorphism) tend to have higher agitation ratings than those who are homozygous for the other form.³⁰ This fits with the broader picture of serotonergic dysfunction in agitation and raises the possibility that genetic testing could eventually help predict which patients are at highest risk, potentially guiding earlier or more targeted intervention.

Wearable Sensors and Early Detection

One of the most frustrating aspects of agitation is its unpredictability. An episode can escalate from mild restlessness to physical aggression in minutes, leaving caregivers scrambling. Emerging digital health tools aim to change that by detecting early warning signs before full-blown agitation develops.

A scoping review of wearable and smart home technologies found that sensors collecting movement data, physiological signals, and sleep information, especially when paired with personalized machine learning models, could reliably detect agitation symptoms and support timely interventions.³¹ A benchmarking study using the largest publicly available dataset for remote monitoring of people with dementia achieved high prediction accuracy by combining in-home activity and sleep data with contextual information like time of day and agitation history.³² These systems are still largely in the research phase, but they represent a shift toward proactive rather than reactive care, which could meaningfully reduce both episodes and caregiver distress.

The practical appeal is easy to see. If a wearable device or a set of home sensors could alert a caregiver that agitation is building, they would have a window to try calming strategies, check for pain or discomfort, or adjust the environment before the situation escalates. For families managing dementia at home, that kind of advance warning could be the difference between a manageable evening and a crisis.