Neuropsychiatric symptoms, habitually labelled as Behavioural and Psychological Symptoms of Dementia (BPSD)1, are almost universally present in Alzheimer's disease (AD), affecting between 90% and 97% of individuals throughout the progression of the disease2–7. These symptoms encompass apathy, depression, anxiety, agitation, and psychosis2, markedly weakening the overall well-being of patients and their care providers, while anticipating a higher speed of operational decline, earlier entry into formal care facilities, and increased mortality2,4. Although their rate of occurrence, NPS remains underappreciated and difficult to deal with and manage due to their intricate biological, psychological, and social fundamental mechanisms2. This review brings together the most recent literature on the biological basis of NPS, highlighting network-level alterations in normal function, impairment in neurotransmitter indices, and amyloid and tau pathology2. We elaborate on certain pathophysiologies for the principal symptom areas and assess existing diagnostic approaches and treatment paradigms. These findings point out the need for a paradigm shift8 toward individual-focused, biomarker-assisted care that merges pharmacological and non-pharmacological techniques9,10. Future improvements rely on improving the quality of the diagnostic set of rules and the formation of targeted interventions that tackle the biological influences of these incapacitating symptoms10
Keywords
Neuropsychiatric Symptoms (NPS), Behavioural and Psychological Symptoms of Dementia (BPSD), Alzheimer's disease (AD), Apathy, Psychosis, Depression
Introduction
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Fig I . Graphical Abstract
Alzheimer's disease11,12 ranks among the most widely observed nerve degeneration disorders globally, characterised mainly by a gradual decline in memory abilities. Increasingly, it is acknowledged that neuropsychiatric symptoms significantly contribute to the disease, rather than merely resulting from memory loss2,13,14. These symptoms often appear during Mild Cognitive Impairment (MCI) and mild behavioural impairment (MBI)15,16, which are the initial phases preceding Alzheimer's disease (AD)2,17–19. Neuropsychiatric symptoms (NPS) encompass a extensive variety of issues20, including emotional symptoms (such as depression and anxiety), psychotic problems (such as delusions and hallucinations), and behavioural changes such as agitation, aggression, and apathy2,10,21. The presence of these symptoms is a more accurate indicator of the necessity for residential care and increased caregiver stress than cognitive decline alone2,22.
BACKGROUND & RATIONALE
The clinical phase of AD is outlined by regression over multiple areas; however, non-cognitive expressions frequently present chief handling difficulties23. This review is necessitated by the fact that, despite the enormous public health effect of NPS, they remain inadequately studied and commonly poorly treated2,4. Prior diagnostic models commonly ruled out NPS as feedback to loss of memory, but recent neuroimaging and biomarker information validate that these symptoms appear from a precise neurobiological weakness1,9,24. By combining the latest breakthroughs in neurobiology and clinical trials, this review aims to furnish a roadmap for more powerful, mechanistically guided initiatives.
PATHOPHYSIOLOGY OF NEUROPSYCHIATRIC SYMPTOMS
The neuroscience of NPS encompasses scattered malfunction over multiple brain regions outside conventional amyloid and tau deposition1,2,24.
Apathy:
widespread disturbances in the neural networks, that is the Salience Network, Default Mode Network (DMN), and locus coeruleus network (LC-NA)1,32.
Role of the Salience Network33: Outside the ACC and OFC, apathy is related to altered function in the Salience Network (SN), which comprises the anterior insula and amygdala1,34,35. This network is vital for assessing external and internal information, and its dysfunction affects emotional numbing and reduces the capability to process emotionally important signals1,36.
Default Mode Network Involvement: Dysfunction within the Default Mode Network, particularly in the dorsomedial prefrontal cortex (DMPFC) and precuneus37, is linked to difficulties in self-motivation and self-awareness37,37,38. This may result in a lack of spontaneous emotional responses or a shortfall in self-initiated ideas25.
Locus Coeruleus-Norepinephrine (LC-NA) System: Apart from dopaminergic pathways, the beginning and significant destruction of the locus coeruleus is a key contributor to early cognitive decline39. This disturbance in the norepinephrine system specifically affects reward processing and cognitive control, further intensifying the motivational challenges40,41.
Figure 2. Key brain networks in goal-directed behaviour and planning31
Certain deficiencies in executive function, including problems with initiation, set-shifting, and abstract thought, are correlated with these physiologic changes. These neuropsychological deficits set the condition of apathy apart from other neuropsychiatric illnesses such as depression.
Depression:
Depression associated with AD is characterised by a complex interaction of structural brain alterations, dysfunction at the circuit level, and neurochemical imbalances, primarily influenced by the fundamental pathology of AD and neuroinflammation42. Structural neuroimaging reveals atrophy in grey matter volume43and cortical thinning, mainly in the frontal and temporal lobes1 b, including areas such as the left dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, anterior cingulate cortex (ACC), hippocampus, and entorhinal cortex44. The alterations affect the frontal-subcortical limbic circuits, where the dorsal section (comprising the DLPFC and dorsal ACC) is responsible for the cognitive elements of mood, while the ventral section (encompassing paralimbic and subcortical areas) controls physical symptoms1,45,46. From a neurochemical perspective, depression is linked with notable impairments in serotonin and norepinephrine due to the lack of cell bodies47 in the dorsal raphe nucleus and locus coeruleus, respectively, which results in decreased levels of these neurotransmitters throughout the brain21,48. These neurotransmitter imbalances are frequently initiated by neuroinflammation, where the stimulation of microglia and the discharge of pro-inflammatory cytokines such as TNF-α and IL-616 further reduce serotonin levels1,9,15,49. This process aligns with the fundamental pathologies of Alzheimer's disease6, as the buildup of amyloid-beta in the frontal lobes and tau in the transentorhinal6 and hippocampal areas is associated with more pronounced symptoms50. Additionally, changes in the hypothalamic-pituitary-adrenal (HPA) axis, marked by elevated cortisol16 indices, facilitate to the persistence of these depressive symptoms over time9,15,51,52.
Psychosis:
The underlying pathology of psychosis in Alzheimer's disease (AD) – typified by the occurrence of delusions and hallucinations - is multifaceted53–55, and includes both neurochemical and anatomical changes as well as genetic and neuropathological causes2,4,56. AD psychosis is biologically different from functional psychotic disorders like schizophrenia, and is generally seen in moderate-to-severe AD56.
Neurochemical Imbalances: AD psychosis is associated with an imbalance in the "monoamine-cholinergic balance".
Dopamine System: Delusions are highly associated with relative hyperdopaminergia in the striatum1. Studies suggest that AD patients having delusions have greater striatal dopamine D2/D3 receptor availability than patients who don’t have delusions46,57. This could be due to the lack of cholinergic neurons51, which normally inhibit the dopaminergic system, while it remains relatively intact1,58. Also, increased dopamine D3 receptor binding in the nucleus accumbens has been found post-mortem56.
Dysfunction of the Serotonin (5-HT) System: There are severe serotonergic abnormalities associated with psychosis58. There is a decrease in 5-HT in the ventral temporal cortex and decreased cell density in the dorsal raphe nucleus56,59. In particular, decreased serotonin levels in the temporal cortex are related to psychosis and hyperactivity1,15,16,60,61.
Cholinergic System: Muscarinic receptors are increased (higher M2 density) in the orbitofrontal gyrus and temporal association cortex in association with delusions56,58,62.
Neuroanatomical and Circuit-Level Dysfunction
AD psychosis has been linked to widespread dysfunction in multiple neural networks, which can manifest as asymmetrical changes1,2.
Delusions: These are mainly associated with frontotemporal lesions, such as left frontal lobe and right temporal lobe atrophy1. Structural imaging studies often reveal hypometabolism in the right lateral frontal cortex, anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC)1,21,63. There is also some evidence of delusions being associated with reduced connectivity in the Default Mode Network (DMN) with the left inferior parietal lobule13.
Hallucinations: These are linked to a disruption of the anterior-posterior neural network, including the dorsolateral prefrontal cortex, occipital lobes and anterior insula1. Visual hallucinations, the most frequent type in AD, are linked with atrophy and white matter lesions of the occipital lobe58.
Salience Network (SN): Dysfunction of the salience network, which informs integrated behavioural and emotional responses, is also believed to be a critical factor in the progression of psychosis64.
Neuropathological Hallmarks
Global amyloid and tau pathology is associated with cognitive impairment, while psychosis is associated with specific pathology.
Amyloid and Tau: Cross-sectionally, increased neuritic plaque density (Aβ) is linked to psychosis65. But tau seems to be more reliable; elevated neurofibrillary tangle density and phosphorylated tau (p-tau) concentrations in the neocortex and frontal cortex of psychosis patients have been observed9,56,60,66psych67.
White Matter Hyperintensities (WMH): Higher WMH volume in the left occipital lobe is a significant predictor of delusions, and whole-brain WMH volume is associated with the severity of delusions68.
Genetics and Risk Factors
Heritability: The estimated heritability of psychosis in AD is 61%, indicating a significant genetic influence56,69,70.
Genetic Variants: The APOE ε4 allele has been connected with an increased risk of psychosis in females9,30,71. There have also been reported associations with common variants in the RP11-541P9.3 antisense transcript and structural copy number variants in the APC2 gene56.
Environmental and Sensory Stimuli: Sensory loss (visual, such as cataracts; auditory) can trigger visual hallucinations and paranoia, respectively56,72. Other acute illnesses (infection, dehydration) and caregiver distress also promote psychosis56.
Figure 3. Conceptual model of psychosis in AD56
Anxiety :
The underlying mechanism of anxiety in Alzheimer's disease is primarily directed attention towards the structural and neurodynamic changes in the amygdala-mediated circuit, which is important for fear interpretation and risk evaluation1,73. Structural magnetic resonance imaging (MRI) shows atrophy of the amygdala and entorhinal cortex74, and atrophy in the right precuneus, inferior parietal lobule, posterior cingulate gyrus and the insula1,75. Structural changes are linked to key functional connectivity changes, including decreased connectivity amid the medial amygdala and the retrosplenial cortex76 (part of the default mode network) and increased local infratemporal connectivity77.
Biologically, these symptoms are connected with preclinical amyloid-beta accumulation in the precuneus, frontal and parietal lobes, and focal tau deposition in the lateral and medial amygdala76,78. Neurochemically, anxiety is linked to abnormalities in the serotonergic, dopaminergic and noradrenergic systems, where the locus coeruleus serves as a key hub for dysfunctional responses to uncertainty79. Additionally, anxiety in AD is increasingly linked to neuroinflammation and is connected to raised interleukin-6 (IL-6) and C-reactive protein (CRP) indices, which may indicate early brain injury, even in the absence of overt cognitive impairment80.
METHODOLOGY
This review presents evidence from a summary of major reviews and original research papers cited in the sources.
Literature Sources and Methods: The literature was searched in major databases (PubMed (MEDLINE), EMBASE, Scopus, and Google Scholar).
Inclusion Criteria: We included studies that included patients with probable AD and MCI (based on NINCDS-ADRDA or DSM-IV/V criteria), reported the prevalence or biological factors associated with NPS, and involved validated instruments such as the Neuropsychiatric Inventory (NPI).
Exclusion Criteria: Manuscripts involving non-AD dementia (unless for comparison purposes), sample sizes less than 10, and patients under 50 years of age were excluded.
Quality Assessment and Data Extraction: Manuscripts were rated for bias and quality using established tools such as the Joanna Briggs Institute-Qualitative Assessment (JBI-QARI) and Newcastle-Ottawa Scale. Extraction of information was done with an emphasis on rates of prevalence, neuroanatomical correlates (MRI/PET), and pharmacotherapy outcomes.
SYNTHESIS OF EVIDENCE
This evidence confirms that NPS are core to AD. Biomarker studies show that decreased CSF Aβ42 and increased p-tau are predictive of longitudinal progression of apathy, depression and anxiety. Also, neuroinflammation (as measured by microglial activation in the ACC and temporal regions) is a predictor of irritability and agitation. A "symptom hypothesis" proposes that these symptoms stem from the same neurodegenerative processes that result in cognitive impairment, whereas a "risk factor hypothesis" suggests that NPS symptoms may be due to coexisting non-AD pathology, like vascular disease15,16.
CURRENT TREATMENTS AND DIAGNOSIS
Diagnosis:
The most commonly utilised instrument of NPS is the Neuropsychiatric Inventory (NPI) or the shorter version, NPI-Q, which both use informant ratings to assess frequency and severity81,82. Other scales include the Geriatric Depression Scale (GDS) and the Cornell Scale for Depression in Dementia (CSDD)83.
Current Treatments:
Pharmacological:
Cholinesterase inhibitors (ChEIs) (such as donepezil) have restricted effects on apathy and overall NPS. Selective serotonin reuptake inhibitors (SSRIs) are used first for depression/anxiety, but are often questioned in large trials for AD84–87.
Antipsychotics are reserved for severe psychosis and agitation because of stroke and death risks88. Newer drugs, such as brexpiprazole and pimavanserin, are promising for symptom subsets.
Non-Pharmacological: These are recommended as first-line interventions. These include caregiver communication training, environmental modifications to minimise distractions and sensory stimulation activities, such as music and art therapy89.
Table 1 ; Major Studies About Neuropsychiatric Diseases In Alzheimer’s Disease
Study Name, Author
Sample Size
Design
Key Findings
DELCODE Study (Sannemann et al., 2020)
687
Longitudinal
NPS in SCD worriers are associated with underlying AD pathology biomarkers (Aβ42).
Cache County Study (Lyketsos et al., 2001)
5,092
Longitudinal
Identified 3 clusters of NPS: 98% of AD patients developed NPS over 5 years.
Amsterdam Dementia Cohort (Eikelboom et al., 2021)
1,515
Observational
NPS were prevalent across th spectrum; apathy and agitation with worse cognitive empairment.
Mayo Clinic Study of Aging (Geda et al., 2014)
1,038
Population Based
NPS like agitation and apathy in cognitively normal persons predict incident MCI.
HABS Cohort (Donovan et al., 2014)
268
Longitudinal
Higher depression scores correlated with lower hippocampal volume in non-depressed, unimpaired subjects.
A4 Study (Li et al., 2024)
598
Preclinical
Focal amygdalar tau binding and connectivity changes relate to early mood symptoms in AD.
FUTURE PERSPECTIVES
Biomarker-driven precision medicine is key to improving NPS2,90. Potential future research directions include virtual reality to improve sensory stimulation and AI monitoring for early detection of changes in behaviour. Incorporating the MBI construct into clinical trials will enable interventions before onset of cognitive deterioration21,91. Further, the role of neuroinflammation and the gut-brain system in regulating behaviour presents an important avenue for drug development92.
CONCLUSION
Neuropsychiatric symptoms are a central, not incidental, feature of Alzheimer's disease4,20. Their multifaceted pathogenesis includes a combination of traditional AD pathology, network deintegration and psychogenic factors24. Although currently available medications have limited efficacy and safety, early recognition of these symptoms through MBI criteria and systematic use of non-pharmacological interventions holds promise for reducing patient and family suffering93. The key to future care is a shift in paradigm that prioritises NPS with the same mechanistic attention as cognitive decline.
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Roselit Mariya
Corresponding author
Department of Pharmacology, St. Joseph’s College Of Pharmacy, Cherthala, Alappuzha, Kerala, India
Surya A.S.
Co-author
Department of Pharmacology, St. Joseph’s College Of Pharmacy, Cherthala, Alappuzha, Kerala, India
Suji P.S.
Co-author
Department of Pharmacology, St. Joseph’s College Of Pharmacy, Cherthala, Alappuzha, Kerala, India
Roselit Mariya *, Surya A.S. , Suji P.S., Perspectives On Neurobehavioural Manifestations Of Alzheimer’s Disease: An Overview, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 10, 3388-3403. https://doi.org/10.5281/zenodo.23577198
10.5281/zenodo.23577198