(AD), have a prevalence of approximately 39–40 per cent1,2. Historically, it is a secondary psychological reaction to memory loss, and existing research indicates that AD pathology leads to anxiety via focal glial-mediated neuroinflammation, interruption of amygdala-related circuits, and HPA-Axis hyper-reactivity3. This review integrates multifaceted data to elucidate anxiety as a base and line clinical manifestation biomarker for abrupt disease progression4. We scanned biological substrates, including strychnine-sensitive glycine receptors and amyloid-beta accumulation. It also investigates the “vicious cycle” in which the psychosomatic burden catalyses neurodegeneration3,5. The latest assessment of biomarker points out that anxiety is a highly influential clinical marker of exacerbated neurodegeneration, demonstrated by markedly raised indices of plasma tau/A?42 ratios even in the starting stages of the AD continuum6. We also point out the interactive risk of coexisting conditions, noting that the aggregation of anxiety and sleeping irregularities can raise the susceptibility to AD advancement by more than fourfold relative to independent symptoms7. Ultimately, we interpret the potential for directing neuroinflammation to attenuate anxiety and to enhance the overall well-being of the augmenting AD population3.
Keywords
Glial-mediated neuroinflammation, HPA-Axis hyper-reactivity, Amyloid-beta, Vicious cycle, AD continuum
Introduction
×
Scope
This article is a wide-ranging, contemporary review. Instead of dwelling on a standalone scenario, it draws together the latest clinical neuroimaging, panel data, and disease-specific animal models to offer deeper insights into how AD-pertinent physiological transformations prompt anxiety.
History
In the past, clinical schemas for AD have centred predominantly on cognitive impairment, chiefly memory deterioration1,8. Neuropsychiatric expressions, such as anxiety, are often underreported, functioning as subordinate outcomes of more complex disorders, particularly depression or psychosis, and are subsumed under the umbrella of “agitation”9. During the closing decades of the 20th century (mid-1990s), a study using the Neuropsychiatric Inventory delineated AD’s behavioural indices and rigorously highlighted anxiety in 48% of individuals.10. The inaugural NINCDS-ADRDA criteria were predicted based on clinical observations, calling for progressive cognitive impairments (e.g., memory and language), but behavioural dysregulation was never taken into account.11. The 2011 NIA-AA guidelines set in motion the preclinical, MCI, and dementia stages, covering biomarkers such as amyloid/tau imaging and CSF, ) which was previously hinged over pure cognition. The 2018 research update and 2016 Mild Behavioural Impairment (MBI) redirected attention toward biological criteria, making it possible to discover before symptoms12,13.
Pathophysiology:
Pathogenesis of Alzheimer's
The pathophysiology of Alzheimer’s disease (AD) is a diverse neurodegenerative process manifested through groups of certain protein clusters14,15.
Amyloid-Beta (Aβ) Plaques:
The primary neuropathological trait that gives a clear meaning to Alzheimer's disease is the accumulation of misfolded protein fragments outside of brain cells3,16–18. These peptides form when the amyloid precursor protein (APP) is broken down by β- and γ-secretases19,20. In future, they come together outside neurons to give rise to neurotoxic oligomers and insoluble senile plaques21,22. This process usually begins in the neocortex and, over time, moves to the hippocampus. It often starts many years before any signs of memory problems appear23,24. Aβ aggregation is believed to disrupt synaptic signal transmission and initiate a cycle of neuroinflammation by activating microglia and astrocytes. The glial cells are capable of sending out pro-inflammatory cytokines, which further promote Aβ synthesis and contribute to neuronal damage25,26. Additionally, everyday factors like sleep disturbances significantly impact this condition, as poor sleep quality is linked to increased Aβ production and impaired mechanisms for clearing it from the brain27,28. Increased Aβ levels have been in relationship with anxiety in connection with neuropsychiatric problems; as set against to those with reduced levels of anxiety, their overlap in incidence estimates a significantly more abrupt decline in verbal memory, executive function, and overall global cognitive performance4,29,30.
Fig 1. Cleavage pathway of the Amyloid protein31
Tau Protein and Its Role:
Different from amyloid aggregation, tau pathology has a foreseeable anatomical pathway known as Braak staging1;
Early Stages (I–II): Pathology usually starts in the transentorhinal cortex and the locus coeruleus24,25.
Intermediate Stages (III–IV): Tau penetrates the medial temporal lobe, impacting regions like the amygdala and hippocampus34. Braak stage 3, which frequently precedes observable memory impairment but coincides with the development of mood symptoms, is when pathological tau in the medial amygdala can first appear35.
Late Stages (V–VI): Significant cognitive and functional decline eventually results from tau buildup reaching the neocortex36.
Before the appearance of substantial amyloid, there was a considerable rise in tau accumulation in the brain stem, midbrain, and hypothalamus—regions critical for controlling sleep and wakefulness27. Orexin levels, a wakefulness marker in the cerebrospinal fluid, are positively correlated with tau protein levels in patients who are having moderate to severe Alzheimer's disease, indicating tau buildup causes sleep disturbances37,38. Tau is commonly used in biomarker tests to assess disease severity. Increased neurodegeneration and a quicker shift in state from moderate cognitive impairment to Alzheimer's dementia are predicted by an elevated tau/Aβ42 ratio in either blood plasma or cerebrospinal fluid39,40.
Fig 2. Pathology of Amyloid and Tau potein in Alzheimers Disease41
Modalities Of AD-Induced Anxiety
Several reinforcing pathophysiological pathways fuel the nexus between AD and anxiety.
Neuroinflammation and Glial Hypothesis
Preliminary results point out that AD pathology (Aβ and tau) induces a chronic inflammatory state. Upregulated microglia can emit pro-inflammatory cytokines, which are TNF-α, IL-6, and IL-8, undermine synaptic plasticity, and then come to a climax with neuronal death in emotional hubs1,42. PET imaging pointed out that focal neuroinflammation in the centromedial amygdala (CMA) and the left inferior occipital region is a strong forecaster of trait-anxiety intensity1. This glial-influenced pathogenesis destroys the amygdala–occipital lobe circuit, which is necessary for managing the emotional generation and processing of threats1.
Structural loss and disruption of brain circuits
Anxiety in AD is connected to a meaningful tissue atrophy in the hippocampus, entorhinal cortex and the right precuneus3,8,27,43. In preclinical AD, subjects have above normal levels of amyloid concentrations, which points to a low level of neural connectivity between the medial amygdala and the retrosplenial cortex (RSC), a principal region of the brain’s resting-state network44,45.The switch from positive connectivity to a significant negative association between these regions aligns with more recorded symptoms of anxiety46.
HPA-Axis Impulsivity & The “Vicious Cycle” Of Stress
AD pathology in the hippocampus/amygdala throws off glucocorticoid negative feedback to the HPA-axis per the Glucocorticoid Cascade Hypothesis47. In the event that this natural guard is depleted, stress hormones are released more frequently, contributing to more damage to vulnerable brain regions5. This gives rise to a raised level of cortisol in humans and corticosterone in rodents. High cortisol levels bring about oxidative stress, compromised mitochondrial function, and further hasten amyloid-beta accumulation and tau hyperphosphorylation, generating a “vicious cycle” in which anxiety propels the neurodegeneration caused by it48,49.
Fig 1. Vicious Cycle50
Neurochemical Alterations: 5-HT, CRF, and NMDA
At the molecular level, AD elicits marked shifts in neurotransmitter systems:
Serotonin and CRF: The serotonergic and corticotropin-releasing factor (CRF)systems are closely intertwined. Dysfunctional operation in these circuits augments sensitivity to stress-induced fear51.
NMDA and Glycine Receptors: Research has pinpointed that AD patients with anxiety shows selective NR2A reduction and GlyR defective functioning in cortical/limbic regions52.
According to recent studies, tau accumulation is a better predictor of neuropsychiatric symptoms like anxiety than amyloid-beta53. The medial and lateral amygdala have markedly elevated indices of deposits of tau protein, which is linked to increased anxiety levels in preclinical AD44. Early-stage anxiety is also known to be caused by tau aggregation in the entorhinal area8.
Spectrum of Alzheimer's Disease
The course of Alzheimer’s disease (AD) is stratified into three stages:
The initial phase, characterised by the absence of visible clinical symptoms, progresses to a stage of amnestic mild cognitive impairment (aMCI), ultimately culminating in the evident dementia associated with Alzheimer’s disease. Amnestic MCI (aMCI) is the highest-risk subtype of MCI, posing a significant risk of advancing to Alzheimer’s Disease54. The fundamental processes involve the formation of amyloid-beta (Aβ) peptide deposits, which trigger a series of subsequent changes, including hyperphosphorylation of tau and neuroinflammation. Additionally, the hallmark characteristics of the disease include senile plaques, resulting from Aβ accumulation, and neurofibrillary tangles, arising from hyperphosphorylated tau proteins. Other contributing factors include neuroinflammation, immune system deterioration, oxidative stress, genetic factors, calcium imbalances, and cholinergic deficits50.
Methdology
Research Methods and Sources:
A comprehensive review was performed by examining literature from key electronic databases such as PubMed, MEDLINE, Embase, PsycINFO, and Web of Science, focusing on studies published in the last 25 years (1995–2020/2025). The search strategy utilized a combination of Medical Subject Headings (MeSH) and free-text terms, including;
Studies were chosen according to the population, exposure, and outcome (PEO) framework57.
Population: consisted of human cohorts of adults who are aged around > 50 along the AD continuum (SCD, MCI, and AD dementia) and recognised transgenic animal models, such as the TgF344-AD rat and 3xTg-AD mouse16,58.
Exposure: Existence of biomarker-validated AD pathology (PET imaging for Amyloid/Tau/TSPO, CSF/plasma ratios of tau/Aβ42) or autopsy-confirmed AD1,2,58.
Outcome: Evaluation of anxiety utilising psychometric tools like the State-Trait Anxiety Inventory (STAI), the Neuropsychiatric Inventory (NPI-Q), or behavioural assays in animals like the Elevated Plus Maze (EPM)1,16,59.
Exclusion Criteria;
The following were excluded from the study to solely direct attention towards AD-specific anxiety:
Studies that consist of dementias other than Alzheimer’s disease (e.g., vascular, Lewy Body, or frontotemporal dementia), unless used as a comparative group.
Case reports, editorials, and non-peer-reviewed grey literature.
Research where anxiety was not evaluated as a unique symptom or where cognitive impairment perplexed the neuropsychiatric measurements.
Quality Assessment and Data Extraction
Methodological quality was analysed by making use of standardised instruments. Observational studies were evaluated using the Newcastle-Ottawa Scale (NOS); randomised controlled trials (RCTs) were appraised via the Cochrane Risk of Bias (RoB 2.0) tool. Data retrieval is directed at sample sizes, diagnostic criteria (e.g., NIA-AA, NINCDS-ADRDA), longitudinal trajectories of symptoms, and neurobiological substrates like amygdalar connectivity and HPA-axis function.
Synthesis of Evidence
Corroborating evidence was brought together employing a narrative approach to characterise pathophysiological pathways and a quantitative summary of frequency and biomarker links. In particular, the review brought together insights on the pooled prevalence of anxiety and the strong connection between amygdalar glial inflammation and trait-anxiety intensity1.
Clinical Manifestations & Biomarker Indicators
Anxiety manifests in various ways over the course of the Alzheimer's disease spectrum60. In Mild Cognitive Impairment (MCI), a notable number of individuals experience anxiety characterized by an intense concern over potential future cognitive decline. Longitudinal research indicates that anxiety in MCI is linked with a 2.5-fold increase in the possibility of progressing to dementia61,62.
Utilizing biomarkers has clarified the onset of these symptoms. Elevated tau/Aβ42 ratios in cerebrospinal fluid and increased levels of plasma phosphorylated tau (p-tau217 and p-tau181) have been linked to anxiety indices over time. Importantly, the Swedish BioFINDER study confirmed that individuals with the highest degree of Aβ pathology experience a significant rise in anxiety indices as time progresses, regardless of their cognitive changes17.
Current Medications and Treatment Conduits
In spite of clinical load, dealing with anxiety in AD stands as a bit tricky, as many established psychotropics offer hardly any efficacy and appreciable safety risks42,59.
Conventional Pharmacotherapy
Cholinesterase Inhibitors (AChEIs): Donepezil, Galantamine and Rivastigmine are the pillars of AD treatment21,57. At the same time, cognitive enhancers can predominantly firm up behavioural symptoms by refining parasympathetic tone in the prefrontal cortex21,27.
NMDA Receptor Antagonists: Memantine is regularly used, notably in moderate-to-severe stages, and has been revealed to have potential in attenuating agitation and anxiety57,63.
SSRIs and SNRIs: Selective serotonin reuptake inhibitors (e.g., Sertraline, Citalopram) are everyday off-label treatments, though their impact on the AD population is unreliable, and they may amplify apathy64.
Novel and Emerging Therapies
The drug development process is now directed against specific AD-related neuropsychiatric pathways21:
KarXT: A coupled M1/M2 muscarinic receptor agonist making a visible promise for reducing the impact of both psychosis and anxiety in AD65,66.
Cannabinoids: Synthetic variants resemble Naboline, and microdoses of THC-based Formulations (IGC-AD1) are getting looked into for lowering the level of agitation and anxiety with diminished side effects compared to conventional antipsychotics67–69.
Brexpiprazole: An atypical antipsychotic that serves the role as a partial agonist at D2, D3 and 5-HT1A receptors, lately making progress in addressing AD-related anxiety70,71.
AVP-786: A multi-drug therapy (deuterated dextromethorphan/quinidine) directed toward sigma-1 and NMDA receptors to alleviate agitation and comorbid anxiety72.
Scientific Disagreements
Causality: The Sequence of Anxiety and Neurodegeneration
A central debate concerns whether anxiety is a consequence of neurodegeneration or a causal risk factor. Some studies suggest that anxiety arises following pathological degeneration in the locus coeruleus73–75. In contrast, other research indicates that persistent trait anxiety elevates the propensity for progression to Alzheimer's disease (AD), suggesting that anxiety may act as a biological catalyst for protein aggregation76,77.
The Awareness Paradox
Scientists are divided on how anosognosia (loss of insight) shapes anxiety in dementia. One approach holds that anxiety minimises as patients become less conscious of their cognitive decline, presenting it as a psychological reaction that dissipates with decreased self-awareness56,78,79. In opposition, neuroimaging facts call into question this view by pointing out that diagnostic indicators of anxiety?fueled neuroinflammation can stick with even in individuals with progressive memory loss who have a deficit in clear perception of their condition80.
Table 1: Key Studies Comparing AD and Anxiety Pathology
Study
Population
Primary Findings
Key Substartes
Yasuno (2024)
19(AD continuum)
Trait anxiety linked to TPSO binding.
Centromedeial Amygdala
Botto (2022)
14,760
Anxiety prevalence peaks at 39-40%.
GlyRS & NMDA Changes
Pietrazk (2015)
333 (Healthy adults)
Anxiety moderates Aβ effect on memory.
Cortical Amyloid Lad
Patel (2024)
212 (Autopsy Confirmed)
Anxiety predicts 2.5x faster progression.
Tau and Aβ Burden
Harris (2023)
3xTG-AD Mouse
Corticosterone increases with age and stress.
HPA-Axis Overdrive
Future Outlook and Strategic Framework
In the days to come, research must give precedence to early biomarker-guided screening to discern individuals in the SCD stage with "anxious-amygdala" phenotype42,80. Incorporating Artificial Intelligence (AI) to keep tabs on digital markers like diurnal behavioural ups and downs in AD, illustrated by Internet of Things (IoT) wearable devices, could put in place of subjective clinician-rated scales81,82. Further to this research, it should spread out into immunologic interventions that keep in check microglial activation as a unique strategy to treat anxiety, while in parallel easing neurodegeneration80.
CONCLUSION
Anxiety as a neuropsychiatric symptom in Alzheimer’s disease is way more than a secondary biological response: it is a neurological defining feature of the disease. Pathophysiological indication affirms that AD-induced neuroinflammation and HPA-axis instability directly cause distress, which later behaves like a vigorous facilitator for cognitive decline. Henceforth, the clinical community should be receptive to a broad-spectrum approach that incorporates novel pharmacology, orienting specific neurochemical systems with biomarker stratification to make changes to the orbit of this overwhelming disease59.
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Roselit Mariya
Corresponding author
Department Of Pharmacology, St. Joseph's College Of Pharmacy, Cherthala
Surya S.
Co-author
Associate Professor, Department Of Pharmcology, St. Joseph’s College Of Pharmacy, Cherthala, Alappuzha
Suji P. S.
Co-author
St. Joseph’s College Of Pharmacy, Cherthala, Alappuzha
Lakshmi S.
Co-author
St. Joseph’s College Of Pharmacy, Cherthala, Alappuzha
Roselit Mariya, Surya S, Suji P. S, Lakshmi S, Alzheimer’s Meets Anxiety: An Overview of Anxiety as an Early Sign and Risk Factor in Alzheimer’s Disease, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 3207-3220, https://doi.org/10.5281/zenodo.20177803
10.5281/zenodo.20177803