Advances in Managing Neuropsychiatric Symptoms of Alzheimer’s Disease: From Early Detection to Emerging Therapies

Introduction & Clinical Burden

Alzheimer’s disease (AD) remains one of the biggest public health challenges worldwide, affecting over 55 million people, with cases expected to nearly triple by 2050 as the population ages.¹ In the US alone, more than 6.9 million people aged 65 and older live with AD, and nearly 1 in 3 seniors dies with AD or another form of dementia.^1,2 This disease is not only a leading cause of death but also a major contributor to disability-adjusted life-years.

Clinically, AD progresses with a gradual decline in cognition, behavior, and functioning, significantly impairing independence and quality of life.³ Neuropsychiatric symptoms (NPS), such as agitation, psychosis, depression, apathy, and sleep issues, are nearly universal during the disease course and quickly worsen functional decline. These symptoms exacerbate caregiving challenges, increase the need for institutional care, and significantly elevate healthcare costs.⁴ Despite their frequency, NPS often go unnoticed and are not sufficiently treated, resulting in unnecessary patient and caregiver suffering as well as more complex care.

The economic impact is equally substantial. The total annual cost of caring for individuals with AD and other dementias in the US is estimated at $360 billion, with Medicare and Medicaid covering nearly two-thirds of this amount.⁵ Indirect costs, such as lost productivity among caregivers, further amplify the societal burden. The projected increase in prevalence underscores the urgent need for better recognition, treatment, and support strategies.^5,6

Why Early Recognition Matters

Early detection of AD and its NPS is crucial for improving outcomes. Research indicates that the early recognition of cognitive decline and behavioral signs enables prompt intervention, enhances patient and caregiver preparedness, and facilitates planning for care transitions.⁷ Additionally, early NPS detection aligns with emerging treatments since disease-modifying therapies (DMTs) and targeted interventions for NPS are most effective when administered during the prodromal or early symptomatic stages of the disease.

Delays in recognition of AD and its NPS continue to be a major contributing challenge. On average, patients experience symptoms for several years before diagnosis, with many reaching moderate stages of the disease before receiving any specialized care.³ During this time, NPS such as depression, anxiety, or subtle behavioral changes are often mistaken for normal aging, stress, or primary psychiatric issues. Misdiagnosis or under recognition leads to inappropriate treatments, delays in lifestyle or medication interventions, and missed chances for clinical trial participation.^8,9

Assessment & First-Line Management^7,10,11

1. Screen routinely for mild behavioral impairment (MBI) and NPS (MBI Checklist, Neuropsychiatric Inventory)
2. Assess safety by prioritizing risks of self-harm or aggression
3. Investigate contributors such as infection, pain, sleep disorders, constipation, dehydration, and polypharmacy
4. Apply the DICE model (Describe, Investigate, Create, Evaluate) for structured interventions

Furthermore, early recognition can lower stigma and promote patient autonomy. As soon as individuals and families understand the diagnosis, they can begin to effectively participate in shared decision-making, adopt compensatory strategies, and access community resources. From a healthcare system perspective, early detection reduces long-term costs by delaying institutionalization, preventing hospitalizations, and avoiding unnecessary prescribing cascades.⁹

The clinical imperative is clear: enhancing clinician confidence in identifying early AD phenotypes as well as associated NPS changes is essential for optimizing care and incorporating emerging therapeutic options.

Phenomenology & Nosology

The clinical presentation of AD goes far beyond memory loss. Patients may show signs of executive dysfunction, visuospatial difficulties, language problems, and a wide range of NPS. These symptoms reflect the diverse biology and progression of the disease, making it challenging for clinicians to differentiate AD from other dementias and psychiatric disorders.¹²

In terms of diagnosis, ongoing efforts aim to improve disease classification by including biomarkers in the criteria. The 2024 National Institute on Aging-Alzheimer's Association (NIA-AA) draft framework emphasizes a biology-based definition of AD centered around amyloid, tau, and neurodegeneration (the “ATN” framework), while also acknowledging the importance of incorporating NPS into staging models.¹³ This change recognizes that psychiatric and behavioral issues are an integral part of the disease, which is linked to specific neural circuit disruptions.^13,14

Recent longitudinal studies highlight that NPS often appear early, sometimes before significant cognitive decline, potentially serving as early indicators of AD pathology. Syndromes like MBI are increasingly recognized as meaningful clinical signs, representing late-life psychiatric symptoms that may signal underlying neurodegeneration.^7,15 This has important implications for both clinical diagnosis and trial design because NPS may offer an early opportunity for intervention.¹² Clinicians need to approach AD classification in a comprehensive manner and understand that the disease affects overlapping cognitive, functional, and behavioral domains. Focusing only on memory could overlook early NPS with prognostic value and impact quality of life.

Pathophysiology & Emerging Evidence

AD pathophysiology is characterized by hallmark amyloid-β plaques and tau neurofibrillary tangles; however, recent research highlights a broader network of neural mechanisms involved in disease progression.¹⁶ Additionally, neuroinflammation, synaptic dysfunction, vascular factors, and mitochondrial impairment are increasingly being recognized as key contributors and drivers. Importantly, these mechanisms also overlap with the development of NPS.¹⁷ Furthermore, dysfunction of the dorsolateral prefrontal cortex disrupts top-down reality monitoring, thereby impairing patients’ ability to evaluate their perceptions and thoughts against external reality.¹⁸ This circuit-level breakdown contributes to the psychotic features seen, such as delusions and hallucinations, which are hallmark NPS of AD. Neuroinflammation, particularly microglial activation, is implicated in both the spread of tau and behavioral issues, providing a biological basis for anti-inflammatory or immunomodulatory therapeutic approaches.¹⁹

Pathophysiology: Circuits, Transmitters, and Pathology

NPS in AD reflect complex, interacting mechanisms^17,20–22:

• Neurotransmitters: dysregulation across serotonergic, dopaminergic, cholinergic, and glutamatergic systems
• Neurocircuitry: agitation linked to anterior cingulate; hallucinations to temporo-occipital changes; delusions to orbitofrontal/cingulate involvement
• Pathology/imaging: amyloid/tau in parietal-temporal cortices and frontotemporal hypometabolism correlate with NPS expression

Additionally, emerging biomarker research is improving the ability to detect early pathophysiologic changes. Advances in plasma and cerebrospinal fluid assays for amyloid, tau, and neurofilament light chain (NfL), along with PET imaging, are allowing for earlier and more precise detection of disease biology and progression.²³ These tools are increasingly used in both clinical practice and trial enrollment, ensuring that patients with early disease stages and relevant NPS are properly and accurately identified. The overlap of pathophysiology and clinical presentation highlights the need for more advanced multidimensional assessment protocols.^24,25 Understanding how specific biological processes relate to symptom domains may guide targeted therapeutic strategies, such as serotonin receptor modulators for agitation or muscarinic agents for psychosis in AD.

Current and Emerging Therapeutics

Therapeutic strategies for AD include symptom management, behavioral interventions, and disease modification. Traditional pharmacological treatments, such as cholinesterase inhibitors and memantine, remain the primary approach for managing cognitive symptoms but offer little to no therapeutic benefits and do not directly target NPS. Managing NPS involves a combination of non-pharmacologic and pharmacologic approaches.²⁶ Behavioral and environmental strategies are considered the first line of defense, although evidence supports the cautious use of medications in severe or refractory cases of psychosis. Antipsychotics such as brexpiprazole have received regulatory approval for agitation in AD, marking an important step forward in targeted NPS treatment.²⁷

Similarly, ongoing research examines serotonergic agents, muscarinic receptor modulators, and TAAR-1 agonists as targeted options for psychosis and agitation, with xanomeline-trospium (XT) showing the most promise, potentially becoming a first-in-class therapy for NPS psychosis. XT is very close to FDA approval for NPS psychosis, pending the upcoming data readout from the ADEPT-2 phase 3 clinical trial.²⁸ Interestingly, the addition of trospium to xanomeline blocks peripheral muscarinic receptors and reduces unwanted anticholinergic side effects while allowing xanomeline to selectively activate central muscarinic M1/M4 receptors in the brain, which enhances efficacy for neuropsychiatric symptoms in Alzheimer’s disease.

Pharmacologic Therapy: What We Know Today

• Muscarinic agonist (xanomeline-trospium) was recently approved for schizophrenia and targets M₁/M₄ muscarinic receptors to rebalance cortical and limbic circuits.
  • Its success in schizophrenia psychosis offers a strong rationale for exploring its potential in AD–related NPS.²⁸
• Antipsychotics offer modest benefit (effect size ≈0.2), but risks include mortality, stroke, sedation, and parkinsonism.²⁹
• Brexpiprazole is the first FDA-approved treatment for AD agitation (2023). It has small to moderate benefit (effect size 0.25–0.35) and better tolerability, but the boxed warning persists.²⁷
• SSRIs: Citalopram reduces agitation at high doses but risks QT prolongation and cognitive decline; use is limited.³⁰
• Dextromethorphan combinations: DM/Q showed phase 2 efficacy but failed in phase 3. AXS-05 showed benefit and relapse prevention but awaits regulatory review.³¹

Future directions include personalized medicine approaches, which use biomarkers and digital tools to tailor treatments. Combining cognitive enhancers, NPS-targeted therapies, and DMTs into an integrated care plan represents the next major step in AD management.

Clinical Pearls for Practice

• NPS are not secondary features but essential to the AD syndrome; clinicians should systematically screen for agitation, depression, psychosis, and apathy.
• Early detection of subtle NPS may serve as an entry point for earlier diagnosis, especially within the new ATN framework.
• When pharmacologic treatment for NPS is necessary, agents with regulatory approval and proven safety in AD populations should be prioritized over off-label options.
• Early detection and diagnosis enable timely access to DMTs, which require biomarker confirmation and are most effective in early-stage disease.
• Non-pharmacologic interventions, caregiver training, and structured psychosocial support remain vital pillars of care.
• Always address triggers before starting any kind of pharmacological therapy.
• Use the lowest effective dose and limit the duration of antipsychotic trials.
• Monitor and reevaluate every 4 to 12 weeks.
• Caregiver education is vital; teach validation, redirection, and environmental modifications.

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