Neuropsychiatric symptoms are a pervasive and challenging aspect of Alzheimer's disease (AD), affecting up to 90% of individuals over the course of the illness.
These symptoms include depression, anxiety, agitation, aggression, delusions, hallucinations and sleep disturbances, each profoundly impacting the quality of life for both patients and unpaid family caregivers. While cognitive decline is the most recognized aspect of AD, neuropsychiatric symptoms often lead to substantial distress, increasing caregiver burden and risk for premature institutionalization. Depression occurs in 30-50% of AD patients, while anxiety is seen in 30-40%; agitation and aggression impact 30-60% of patients, and psychotic symptoms (e.g., delusions and hallucinations) appear in 20-30% of cases. Variability in these symptoms is influenced by factors such as disease stage, patient demographics and assessment methods, complicating treatment efforts.
The neuropathological basis of neuropsychiatric symptoms in AD
The development and progression of neuropsychiatric symptoms are closely tied to the underlying neuropathological changes in AD. As cognitive decline advances, it impairs regions of the brain essential for mood regulation, emotion and behavioral control. Neurochemical imbalances, structural changes in the brain, and inflammatory responses are primary contributors. Depression and anxiety in AD, for instance, are not solely due to psychological responses to functional decline and losses but have roots in neurochemical shifts that disrupt normal emotional processing. These shifts are exacerbated by AD-related damage to areas such as the limbic system, which governs emotion, and the prefrontal cortex, essential for decision-making and impulse control. Psychotic symptoms, including delusions and hallucinations, emerge from disruptions in neurotransmitter systems, notably dopamine and serotonin, which play roles in perception and reality testing.
Sleep disturbances, prevalent in AD, result from circadian rhythm disruptions and changes in sleep architecture, worsened by damage to brain regions that regulate sleep. Neuropsychiatric symptoms, combined with comorbidities like depression, increase the likelihood of disordered sleep, complicating overall care. As AD progresses, aggressive and agitated behaviors become more common, likely due to damage to emotional regulation centers and the impact of external stressors on individuals with a diminished capacity for coping. Specific personality traits and the presence of additional stressors, such as ineffective behavioral management approaches, absent or limited compensatory support for diminishing cognitive abilities, unfamiliar or unsupportive environments, can further intensify these symptoms.
Monoclonal antibody therapies and their role in AD
Recent advancements in monoclonal antibody treatments for AD, particularly those targeting amyloid pathology in early stages of the disease, have transformed the landscape of AD therapy. Medications like lecanemab and aducanumab are designed to slow disease progression by targeting and reducing amyloid-beta plaques, a hallmark of AD pathology. Although promising, it is essential to remember that while monoclonal antibodies may impact the neuropathology underlying AD and potential trajectory of cognitive decline, they do not directly address the neuropsychiatric symptoms that often define the patient’s experience and quality of life, nor is every patient an appropriate candidate for such therapy. Neuropsychiatric symptoms require a nuanced approach, even when disease-modifying treatments are in place, as the emotional and behavioral manifestations of AD are complex and multifactorial.
Non-pharmacological approaches: The first line of intervention
Given the multifaceted nature of neuropsychiatric symptoms, non-pharmacological or behavioral strategies are widely regarded as the initial line of treatment. These interventions aim to improve patient and caregiver well-being in a holistic manner without the side effects associated with pharmacological treatments. Central to these approaches is person-centered care for dementia, which focuses on the individual’s unique needs, preferences and history to create a supportive environment that alleviates distressing symptoms and improves quality of life.
As an unofficial extension of the medical team, caregivers play an instrumental role in delivering individualized, behavioral interventions to their loved ones, often under stressful and challenging circumstances. Adding to the complexity are ever-changing neuropathological, personality and environmental factors. Unfortunately, caregivers often lack adequate support and training to deliver interventions, particularly under changing conditions, increasing their overall burden and stress, and contributing to premature patient institutionalization.
Early and ongoing collaboration with caregivers is key to assessing evolving support and training needs with the use of behavioral strategies. These strategies improve quality of life for patients and caregivers while building caregivers' master and self-efficacy in behavioral management.
- Behavioral strategies and psychosocial support: Behavioral therapy, adapted for AD patients, can help caregivers by identifying triggers for distressing behaviors and use of adaptive coping strategies. Techniques such as redirection and reassurance can help patients feel secure, reducing anxiety and mild depression. Psychosocial support, involving both family and professional caregivers, creates a structured, positive environment that reduces distress for both patients and caregivers.
- Environmental modifications: Modifying the patient’s physical surroundings can significantly impact symptom management by reducing stimuli that may lead to confusion or frustration. For example, reducing background noises, improving lighting, and maintaining consistent routines can help patients feel less anxious and promote independence.
- Sensory stimulation and relaxation techniques: Sensory interventions, including music therapy, aromatherapy, and gentle tactile stimulation, may offer calming effects that can reduce agitation and aggression.
- Exercise and Physical Activity: Regular physical activity, such as walking, tai chi, or chair-based movements, can support physical fitness, healthy sleep rhythms and emotional wellness. Exercise promotes the release of serotonin and endorphins, which enhance emotional well-being and reduce neuropsychiatric symptoms.
- Reminiscence Therapy and Life Review: Reminiscence therapy encourages patients to discuss past experiences using familiar objects, music, or photographs. This approach strengthens a sense of identity, reduces depression and agitation, and fosters connections with caregivers.
- Engagement in meaningful activities: Participating in activities that reflect the patient’s interests and hobbies, such as creative art activities, gardening, or simple household tasks, can provide a sense of purpose and can lessen mood and anxiety symptoms. Regular engagement in activities scaled to the patient’s abilities can improve quality of life and lessen triggers for behavioral disturbances.
Pharmacological approaches: Limited use and caution
Pharmacological interventions are generally reserved for cases in which non-pharmacological methods are clinically insufficient. When medication is necessary, careful consideration of side effects and dosing is crucial due to the potential for adverse reactions in older adults with AD.
- Antidepressants and antipsychotics: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used to manage depression and anxiety in AD patients. For more severe symptoms, such as agitation and psychosis, atypical antipsychotics may be considered. Brexpiprazole, for example, was approved by the FDA in 2023 specifically for AD-related agitation. It acts as a partial agonist at serotonin and dopamine receptors and helps stabilize mood and reduce agitation without the heavy sedative effects seen in other antipsychotics.
- Cholinesterase inhibitors and NMDA receptor antagonists: Medications like donepezil and memantine are used to enhance cognitive function in AD, particularly in moderate to severe cases. While primarily targeting cognitive symptoms, these medications may also indirectly improve neuropsychiatric symptoms by enhancing overall brain function.
Balancing disease-modifying and symptomatic treatments
The advent of monoclonal antibodies represents a critical advancement in AD care, offering hope in slowing cognitive decline and disease progression in the early stages. However, the persistence of neuropsychiatric symptoms across the disease continuum necessitates that treatment strategies encompass both the physiological and psychological aspects of AD. As monoclonal antibodies alter the neuropathological landscape of AD, attention to neuropsychiatric symptom management remains indispensable. These symptoms, rooted in complex neurobiological processes and exacerbated by environmental and psychosocial factors, require an ongoing, integrated treatment model that combines disease-modifying therapies with symptom and behaviorally focused care.
Towards an integrated model of care: Enhancing quality of life for patients and caregivers
Considering recent therapeutic advances, a comprehensive care model that includes both monoclonal antibody therapies and a robust approach to neuropsychiatric symptom management is essential.
Non-pharmacological interventions, tailored to each patient and caregiver and implemented within a structured, supportive environment, offer meaningful improvements in quality of life while minimizing the need for pharmacological intervention. Medications, when needed, should be prescribed cautiously with close monitoring to ensure efficacy and safety. By combining targeted therapies, the treatment pathway prioritizes safety, quality of life, and respect for each individual with AD.
Through this balanced and compassionate approach, the treatment of neuropsychiatric symptoms in AD aligns with the principles of person-centered care for dementia, creating a therapeutic pathway that addresses the physical, emotional, and social dimensions of the disease. This comprehensive strategy supports both the patient and caregivers, fostering a therapeutic environment where dignity, safety, and quality of life is prioritized in the face of a challenging illness.
Neuropsychiatric symptoms in Alzheimer's disease: A neuropsychiatrist and psychologist's perspective on comprehensive care and treatment
Neuropsychiatric symptoms (NPS) are an inevitable and often distressing aspect of Alzheimer’s disease that affect up to 90% of individuals over the course of their illness. We have witnessed how these symptoms — from depression, anxiety, and agitation to psychotic features like delusions and hallucinations — create significant challenges and disruptions to both patients and their caregivers. These symptoms are critical to manage, as they profoundly impact patients' quality of life, increase caregiver burden, and elevate the risk of institutionalization.
While the cognitive decline characteristic of AD may overshadow other symptoms, it is the neuropsychiatric aspects that frequently define the daily experience of patients and families. In fact, caregivers consistently rank neuropsychiatric symptoms as more distressing than cognitive decline or associated functional losses. Understanding and addressing these symptoms, which range in prevalence from 30% to 60% for conditions like depression, anxiety, and agitation, requires a care approach that is as multifaceted and nuanced as the disease itself. The pathophysiology behind these symptoms, including neurochemical imbalances, inflammatory processes, and structural brain changes, presents both unique challenges and opportunities for neuropsychiatrists and psychologists to deliver patient-centered care.
Creating a Comprehensive, Person-Centered Model of Care
An integrated care model that includes both psychological interventions and neuropsychiatric symptom management highlights the neuropsychiatrist's and psychologist's shared commitment to comprehensive treatment. Through consistent and continuous caregiver support and training, non-pharmacological interventions can offer both patients and caregivers meaningful relief, while pharmacological treatments are used sparingly and with clear purpose. By prioritizing safety, quality of life, and respect for each individual living with dementia, neuropsychiatrists and psychologists work collaboratively to deliver care that goes beyond the disease’s biological aspects by honoring each patient’s dignity, preferences, personhood, and caregiver team.
Through this therapeutic approach, neuropsychiatric symptoms in AD can be managed in a way that aligns with person-centered care principles while emphasizing safety, quality of life, and respect for patients and caregivers. Our goal is to support both patients and caregivers, fostering a therapeutic environment where dignity, comfort, and emotional security are paramount.