Elevated CSF Serotonin in Prodromal Alzheimer’s Disease Patients Developing Psychosis
by
, ,
Victoria Monge-García
1,2,
Rocío Pérez-González
2,3,4,*,
Sonia Monge-García
5,
Ruth Gasparini-Berenguer
2,
José Sánchez-Payá
2,6,
Raissa de Fátima Silva-Afonso
6 and
José-Antonio Monge-Argilés
2,7,* 1
Physical Medicine and Rehabilitation Section, Hospital Marina Baixa, 03010 Alicante, Spain
2
Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Avda. Pintor Baeza 12, 03010 Alicante, Spain
3
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández–CSIC, 03010 Alicante, Spain
4
Centro de Investigación en Red–Enfermedades Neurodegenerativas (CIBERNED), 03010 Alicante, Spain
5
Neurologiedienst, St. Augustinos Hospital, 52355 Düren, Germany
6
Preventive Medicine Section, Hospital General Universitario Dr. Balmis, 03010 Alicante, Spain
7
Department of Neurology, Hospital General Universitario Dr. Balmis, ISABIAL, Avda. Pintor Baeza 12, 03010 Alicante, Spain
*
Authors to whom correspondence should be addressed.
J. Dement. Alzheimer's Dis. 2026, 3(1), 14; https://doi.org/10.3390/jdad3010014
Submission received: 6 December 2025
/
Revised: 16 January 2026
/
Accepted: 26 February 2026
/
Published: 13 March 2026
(This article belongs to the Special Issue Risk Factors, Intervention and Prevention of Dementia and Alzheimer's Disease)
Abstract
Introduction: Psychotic symptoms (PS) in Alzheimer’s disease (AD) are associated with unfavorable prognosis, including accelerated functional decline and reduced survival. Multiple neurotransmitter systems have been implicated in the pathophysiology of PS, with the serotonergic system emerging as particularly relevant. Materials and Methods: Between 2010 and 2020, 120 patients with prodromal AD and 26 cognitively healthy controls underwent comprehensive evaluation, including clinical history, neurological and neuropsychological assessment, neuroimaging, and lumbar puncture. All participants underwent longitudinal clinical monitoring for a minimum of five years or until the emergence of PS. In February 2024, baseline cerebrospinal fluid (CSF) serotonin (5-HT) concentrations were quantified using competitive ELISA (FineTest, Wuhan, China). Results: CSF 5-HT levels were significantly elevated (p < 0.003) in patients who subsequently developed psychosis (n = 49) compared with those who remained free of PS during the 8-year follow-up (n = 19). A threshold of 4.89 ng/mL yielded 80% sensitivity for identifying individuals at risk. Baseline Neuropsychiatric Inventory (NPI; p < 0.001) and Unified Parkinson’s Disease Rating Scale part III (UPDRS III; p < 0.009) scores also demonstrated strong discriminative capacity. Conclusions: Measurement of CSF 5-HT and detailed clinical profiling in prodromal AD may provide predictive value for psychosis onset within 8 years of diagnosis. To our knowledge, this is the first study to report CSF 5-HT findings in AD patients.
1. Introduction
Alzheimer’s disease (AD) is the most prevalent form of dementia. Its hallmark neuropathological features include extracellular deposition of amyloid-β (Aβ) plaques and neurofibrillary degeneration of hyperphosphorylated tau proteins. These alterations are reflected in the cerebrospinal fluid (CSF) biomarkers, typically as reduced Aβ1-42 concentrations and elevated phosphorylated tau, although numerous additional protein changes have been reported, reflecting diverse metabolic pathways potentially disrupted in the brain [1,2,3,4,5,6,7,8].
The concept of prodromal AD has been established over the past decade, supported by evidence that individuals presenting with predominantly amnestic cognitive impairment and positive AD biomarkers—either imaging or CSF—are highly likely to progress to the clinical stage of the disease [9].
Psychotic symptoms (PS) are recognized as a major adverse prognostic factor in dementias, associated with accelerated functional decline and reduced survival [10,11,12]. This subgroup is estimated to represent 30–40% of AD cases [9], with significant implications for patients, caregivers and healthcare systems.
In a previous study [13], our group demonstrated that the measurement of alpha-synuclein (AS) in CSF, a putative biomarker of the dopaminergic pathway, exhibited high sensitivity (around 80%) in differentiating AD patients with and without PS during disease progression. However, specificity was low (around 40%), limiting its utility as a standalone biomarker. This finding was anticipated, given that the emergence of PS involves multiple neurotransmitter systems, including cholinergic, serotonergic, and GABAergic pathways, in addition to dopaminergic [14].
Serotonin (5-HT) is a pivotal neurotransmitter that regulates a broad spectrum of physiological functions [15] and plays a central role in multiple domains of cognition and human behavior, including appetite regulation, mood disorders such as depression and anxiety, and aggressivity, as well as the emergence of hallucinations and delusions [15,16]. The effects of 5-HT are mediated through its receptors, particularly 5-HT2A and 5-HT2C [16]. Several studies have reported that 5-HT2C receptor activity is associated with delusional phenomena and hallucinations in patients with AD [17,18]. Aberrant serotonergic signaling has been shown to correlate significantly with PS in AD [19]; however, direct mechanistic evidence delineating how serotonergic dysfunction contributes to psychosis in AD remains elusive [15]. To the best of our knowledge, despite converging evidence implicating serotonergic pathways in AD-related psychosis, CSF levels of 5-HT have not yet been systematically investigated to clarify this relationship.
Objective
In the present study, we investigated CSF serotonin (5-HT) concentrations in a cohort of prodromal AD patients to assess their diagnostic validity in predicting PS within eight years of diagnosis. Additionally, we evaluated the predictive value of detailed neurological examination and Neuropsychiatric Inventory (NPI) scores during the prodromal phase.
2. Materials and Methods
2.1. Study Design
This was a retrospective observational cohort study.
2.2. Study Population
Between 2010 and 2020, patients with mild cognitive impairment (MCI) evaluated at the Dementia Clinic of Hospital General Universitario de Alicante (HGUA) underwent comprehensive clinical, neurological, neuropsychological, laboratory, and neuroimaging assessment. Lumbar puncture (LP) was performed in cases of diagnostic uncertainty. Twenty-six cognitively normal individuals undergoing LP for headache were included as controls.
2.3. Inclusion Criteria for LP
- Age > 55 years;
- Mini-Mental State Examination (MMSE) ≥ 24;
- Informant questionnaire score < 78;
- Written informed consent.
2.4. Inclusion Criteria for This Study
- Diagnosis of AD according to NIA-AA 2011 clinical criteria and NIA-AA 2018 laboratory criteria [9];
- Minimum 5-year follow-up unless psychosis developed earlier.
2.5. Exclusion Criteria for LP
- Dementia at baseline;
- Neurological, psychiatric, or medical conditions causing cognitive impairment;
- Anticoagulation therapy;
- Lack of consent;
- Yesavage Geriatric Depression Scale score > 5.
2.6. Exclusion Criteria for This Study
AD patients who did not develop PS within the first 8 years of disease progression.
2.7. Clinical Procedures
Patients were reassessed every 6–12 months. All were diagnosed with AD within 2 years of LP and initiated treatment with acetylcholinesterase inhibitors. Psychosis was defined as NPI (hallucinations + delusions) > 9, after excluding acute illness, delirium, or medication changes [20].
2.8. CSF Collection and Processing
CSF samples were collected between 10 a.m.–2 p.m. using 20 × 3.5 gauge needles. Samples were centrifuged at 2000× g for 10 min, and the supernatant aliquoted in polypropylene tubes, and stored at −80 °C. Only samples with <50 RBCs were included in the analysis.
2.9. Measurement of Core AD Biomarkers
Aβ42, total tau, and phosphorylated tau (p-tau 181) were measured using commercial ELISA kits (Innotest, Ghent, Belgium). Abnormality thresholds followed NIA-AA 2018 criteria [9].
2.10. Measurement of Serotonin (5-HT)
CSF serotonin levels were measured simultaneously in 2024 using a competitive-ELISA detection method (EU0253, FineTest, Wuhan, China) by following the provider instructions. Briefly, the 96-well plates coated with ST/5-HT(5-hydroxytryptamine) were washed twice before adding 50 µL of standards or undiluted CSF samples in duplicate. An equal volume of biotin-labeled antibody was added immediately and incubated for 45 min at 37 °C. After three washes, 100 µL of HRP–streptavidin conjugate was added, followed by a 30-min incubation at 37 °C. Plates were then washed five times, developed with 90 µL TMB substrate for 15 min at 37 °C, and stopped with 50 µL stop solution. Absorbance was measured at 450 nm, and serotonin concentrations were calculated from the standard curve.
2.11. Statistical Analysis
Parametric and non-parametric tests were applied as appropriate. Odds Ratio (OR), survival curves, and Hazard Ratios (HR) were used to evaluate predictive variables, and receiver operating characteristic (ROC) analyses were used to evaluate the diagnostic accuracy of CSF 5-HT. Statistical significance was set at p < 0.05.
2.12. Ethical Considerations
The study was approved by the Ethics Committee of Hospital General Universitario Dr. Balmis (Reference PI2023-27, January 2023).
2.13. Limitations
Main limitations include the single-center design and absence of neuropathological confirmation. We acknowledge the potential variability of CSF 5-HT measurements over long-time storage and batch analysis as an additional limitation.
3. Results
3.1. Included Population
Figure 1 illustrates the distribution of patients across groups in February 2024, according to the presence of PS and control subjects. Of the 120 AD patients enrolled, 49 developed PS, while 19 remained symptom-free for eight years or longer following diagnosis. An additional 52 patients had not yet reached this follow-up period and were therefore excluded from the analysis because the emergence of PS within the first 8 years of disease progression could not be ruled out.
3.2. Baseline Characteristics
Table A1 (Appendix A) summarizes the clinical and laboratory characteristics of prodromal AD patients, stratified by PS status, as well as those of the control group. The proportion of patients receiving serotonin reuptake inhibitor therapy did not differ significantly between groups (p < 0.1).
Table A2 (Appendix A) demonstrates the absence of significant differences across the evaluated variables when comparing AD-PS and AD-NoPS groups collectively.
3.3. Comparison Between AD-PS and AD-NoPS Groups (8 Years Post-Diagnosis)
Table A3 (Appendix A) presents the factors associated with PS development in AD patients. CSF 5-HT concentrations (p < 0.003), NPI scores (p < 0.001), and Unified Parkinson’s Disease Rating Scale part III (UPDRS III) scores (p < 0.009) emerged as the most discriminative variables between groups. The proportion of patients treated with serotonin reuptake inhibitors again showed no significant differences (p < 0.5).
3.4. Predictive Analysis
Figure 2 depicts the probability of PS onset as a function of CSF 5-HT concentrations (A) (≤7.7 versus >7.7 pg/mL), NPI scores (B) (<4 versus ≥4), and UPDRS III scores (C) (≤1 versus >1), relative to disease duration following diagnosis.
In the initial multivariable analysis (Figure 3), several clinical factors showed a significant association with the risk of the PS. Elevated serotonin levels (>7.7 ng/mL) were associated with an increased risk (HR 1.9; 95% CI: 1.1–3.6). Similarly, reduced cognitive performance (MMSE < 27) was linked to a higher risk (HR 2.0; 95% CI: 1.1–3.6). Clinically relevant neuropsychiatric symptoms (NPI ≥ 4) demonstrated a robust association (HR 3.4; 95% CI: 1.8–6.6), and extrapyramidal motor signs (UPDRS III > 1) emerged as the strongest predictor (HR 3.9; 95% CI: 2.0–7.4). In contrast, sex, age, basic functional status (Barthel Scale), and instrumental activities of daily living (Lawton-Brody scale) did not show significant associations.
In the adjusted model1, elevated serotonin levels remained significantly associated with the risk (HR1 1.9; 95% CI: 1.1–3.5). Neuropsychiatric symptoms continued to be an independent predictor (HR1 2.4; 95% CI: 1.2–4.8), as did extrapyramidal motor signs (HR1 2.7; 95% CI: 1.4–5.3). The effect of MMSE < 27 was attenuated and no longer reached statistical significance (HR1 1.6; 95% CI: 0.9–2.8). None of the demographic or functional variables achieved statistical significance after adjustment.
3.5. ROC Analysis
Figure 4 displays the ROC curve. At a threshold of 4.89 ng/dL, sensitivity for distinguishing between groups was 80%, with a specificity of 53%. The calculated area under the curve was 0.78.
4. Discussion
In this study, we observed elevated CSF 5-HT concentrations in prodromal AD patients who subsequently developed psychosis. To our knowledge, this is the first report in the medical literature documenting this association through direct CSF measurement.
Serotoninergic dysfunction has long been linked to psychosis in AD [11,15,16,18,19,21,22], although the precise mechanisms remain incompletely understood. Prior investigations suggest that excessive activation of 5-HT2A receptors may precipitate PS [12]. Conversely, antagonism or negative modulation of 5-HT2A receptors has demonstrated efficacy and tolerability in the treatment of AD psychosis [16,18], underscoring the therapeutic relevance of agents targeting this pathway.
Neuropathological studies consistently reveal alterations in 5-HT2A receptors in AD-PS patients [22,23]. Furthermore, silent mutations at position 102 (T102C) in the 5-HT2A receptor gene have been proposed as a potential risk factor for PS in AD [16]. Our findings exhibit altered CSF 5-HT concentrations in patients destined to develop psychosis, suggesting that monitoring this biomarker may aid in prediction and possibly prevention of PS in AD. Importantly, the absence of significant differences in serotonin reuptake inhibitor use between groups rules out pharmacological treatment as a confounding factor.
The elevation of CSF serotonin observed in our patients with psychosis may reflect, among other mechanisms, increased activation of mast cells—major sources of serotonin—leading to enhanced neurotransmitter release and amplified neuroinflammatory responses, which could ultimately contribute to the poorer clinical prognosis observed in these individuals [10,11,12,13,14,15,16,17].
Our findings may contribute to predicting the onset of PS in AD. Nevertheless, serotonergic dysfunction alone cannot fully account for psychosis in AD patients. Other neurotransmitter systems—including dopaminergic, GABAergic, and cholinergic pathways—have also been implicated [14,23]. In our 2023 publication, we demonstrated that α-synuclein levels predicted PS onset in AD, reflecting dopaminergic involvement. Although sensitivity was acceptable (80%), specificity was limited [13]. The present findings, which parallel those results, highlight the need for integrated predictive models combining multiple biomarkers to enhance accuracy in forecasting psychosis onset, particularly through CSF protein profiling.
We also emphasize the clinical utility of neurological and neuropsychological assessment in patients with MCI. The presence of extrapyramidal signs on neurological examination or an NPI score ≥ 4 in amnestic MCI patients should raise concern regarding the potential development of PS in the years following AD diagnosis. In the prodromal stage of Alzheimer’s disease, an NPI score ≥ 4 may reflect either a genetic and/or acquired predisposition [11,14], or the involvement of brain regions susceptible to psychotic manifestations. Specifically, dysfunction within the mesolimbic circuit, projecting from the ventral tegmental area to the nucleus accumbens, has been demonstrated to promote positive symptoms such as hallucinations and delusions [23]. Furthermore, the detection of extrapyramidal signs using the UPDRS III scale may indicate concomitant α-synuclein pathology, thereby facilitating the emergence of psychotic symptoms through its clinical overlap with dementia with Lewy bodies [11].
Given the multiple factors influencing prognosis in AD, we selected an eight-year disease duration threshold as the boundary for PS onset, consistent with the reported mean survival following AD diagnosis [24]. Beyond this period, additional medical conditions may contribute to psychosis, not necessarily attributable to AD itself.
Main limitations include the single-center design and absence of neuropathological confirmation. We acknowledge the potential variability of CSF 5-HT measurements over long-time storage and batch analysis as an additional limitation.
In summary, this study provides the first evidence that elevated CSF 5-HT concentrations are detectable in prodromal AD patients who later develop PS. This novel finding aligns with prior literature and supports the potential of CSF 5-HT as a predicting biomarker, opening new perspectives for early intervention strategies in AD.
5. Conclusions
We present the first evidence that elevated CSF 5-HT levels in prodromal AD are associated with future psychosis. Combined biomarker and deep clinical assessments may improve early risk stratification.
Author Contributions
Conceptualization, J.-A.M.-A.; Methodology, J.-A.M.-A.; Formal analysis, R.P.-G., J.S.-P. and R.d.F.S.-A.; Investigation, V.M.-G., S.M.-G. and J.-A.M.-A.; Resources, R.G.-B.; Writing—original draft, R.P.-G., S.M.-G., J.S.-P. and J.-A.M.-A.; Writing—review & editing, V.M.-G. and J.-A.M.-A. All authors have read and agreed to the published version of the manuscript.
Funding
This research was partially funded by Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), grant number 20389-2023.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Hospital General Universitario Dr. Balmis (Reference PI2023-27, 27 January 2023).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data sets presented in this article are not readily available because the data are part of an ongoing study. Requests to access the data sets should be directed to José-Antonio Monge-Argilés.
Acknowledgments
We would like to thank the Biobank of the Hospital General Universitario Dr. Balmis in Alicante for their excellent management of the cerebrospinal fluid (CSF) samples. We also gratefully acknowledge the staff of the Polivalente Unit of the Hospital General Universitario Dr. Balmis in Alicante for their collaboration in the collection of the samples.
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript:
| AD | Alzheimer’s disease |
| PS | Psychotic symptoms |
| CSF | Cerebrospinal fluid |
| 5-HT | Serotonin |
| NPI | Neuropsychiatric Inventory |
| UPDRS III | Unified Parkinson’s Disease Rating Scale part III |
| LP | Lumbar puncture |
| MCI | Mild cognitive impairment |
| ROC | Receiver operating characteristics |
| OR | Odds Ratio |
| RBC | Red blood cells |
| NIA-AA | National Institute of Aging and Alzheimer’s Association |
| ELISA | Enzyme-Linked Immunosorbent Assay. |
| HRP | Horseradish Peroxidase |
| TMB | Tetramethylbenzidine |
Appendix A
Table A1.
Comparison between patients and control group included in the study.
| NO PS-AD GROUP (n = 71) | PS-AD GROUP (n = 49) | CONTROL GROUP (n = 26) | S. L. | |
|---|---|---|---|---|
| AGE (mean ± SD) | 73.0 ± 6.1 | 72.3 ± 6.4 | 68.3 ± 7.1 | 0.1 |
| GENDER M/F (%M) | 30/41 (42) | 18/31 (36.7) | 13/13 (50) | 0.1 |
| APOE GENOTYPE ε2 (%) ε3 (%) ε4 (%) | 2 (3) 33 (46) 19 (26) | 0 (0) 28 (57) 11 (23) | 1 (4) 14 (53) 1 (4) | 0.2 |
| MMSE (median p25–p75) | 25.2 (23–26) | 24.6 (23–26) | 28 (26–28) | 0.05 |
| BARTHEL Schelle (mean ± SD) | 99.1 ± 2.1 | 98.6 ± 2.3 | 99.4 ± 3.4 | 0.1 |
| LAWTON-BRODY (median p25-p75) | 5.94 (4–8) | 5.46 (4–8) | 6.84 (6.5–8) | 0.2 |
| NPI (median p25-p75) | 3.3 (0–4) | 5.5 (0–8) | 5.9 (0–10) | 0.05 |
| UPDRS III (median p25-p75) | 0.34 (0–1) | 1.71 (0–4) | 0 | 0.02 |
| CSF 5-HT LEVELS (pg/dL) (median p25-p75) | 6.07 (2–8) | 7.09 (2–12) | 6.26 (3–7) | 0.05 |
| CSF Aβ42 LEVELS (pg/dL) (median p25-p75) | 653.56 (489–676) | 557.18 (472–652) | 1133.2 (940–1403) | 0.0001 |
| CSFT-TAU LEVELS (pg/dL) (median p25-p75) | 720.18 (419–768) | 590.95 (337–718) | 222.69 (166–246) | 0.0001 |
| CSF P-TAU 181 LEVELS (pg/dL) (median p25-p75) | 112.4 (75–118) | 87.78 (60–98) | 37.9 (34–49) | 0.0001 |
| SSRI TREATMENT (%) | 24 (34) | 15 (31) | 14 (53) | 0.05 |
MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; UPDRS III: Unified Parkinson’s disease rating scale. SSRI: selective serotonin reuptake inhibitors. S. L.: Signification level.
Table A2.
Characteristics of the Alzheimer’s patients following the serotonin levels (n = 120).
| Total | Serotonin > 7.74 | Serotonin < 7.74 | p | |
|---|---|---|---|---|
| n (%) | n (%) | n (%) | ||
| Total | 120 (100) | 30 (25) | 90 (75) | - |
| Gender | 0.331 | |||
| Men | 47 (39.2) | 14 (46.7) | 33 (36.7) | |
| Woman | 73 (60.8) | 16 (53.3) | 57 (63.3) | |
| Age | 0.594 | |||
| <68 years | 24 (20.0) | 8 (26.7) | 16 (17.8) | |
| 68–72 years | 27 (22.5) | 6 (20.0) | 21 (23.3) | |
| 73–77 years | 37 (30.8) | 7 (23.3) | 30 (33.3) | |
| >77 years | 32 (26.7) | 9 (30.3) | 23 (25.6) | |
| APOE genotype | 0.609 | |||
| 3 | 33 (47.8) | 10 (43.5) | 23 (50.0) | |
| 4 | 36 (52.2) | 13 (56.5) | 23 (50.0) | |
| MMSE | 0.459 | |||
| 24–27 | 55 (45.8) | 12 (40.0) | 43 (47.8) | |
| >27 | 65 (54.2) | 18 (60.0) | 47 (52.2) | |
| Barthel Schelle | 1.000 | |||
| 90–95 | 13 (10.8) | 3 (10.0) | 10 (11.1) | |
| 100 | 107 (89.2) | 27 (90.0) | 80 (88.9) | |
| Lawton-Brody Schelle | 0.292 | |||
| 0–5 | 58 (48.3) | 17 (56.7) | 41 (45.6) | |
| >5 | 62 (51.7) | 13 (43.3) | 49 (54.4) | |
| NPI | 0.289 | |||
| ≥4 | 66 (55.0) | 19 (63.3) | 47 (52.2) | |
| 0–4 | 54 (45.0) | 11 (36.7) | 43 (47.8) | |
| UPDRS III | 0.486 | |||
| >1 | 18 (15.0) | 5 (16.7) | 13 (14.4) | |
| 0 | 102 (85.0) | 25 (83.3) | 77 (85.6) |
MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; UPDRS III: Unified Parkinson’s disease rating scale.
Table A3.
Associated factors to the development of psychosis in prodromal Alzheimer’s disease patients. AD-PS group versus no AD-SP after 8 years of evolution.
Table A3.
Associated factors to the development of psychosis in prodromal Alzheimer’s disease patients. AD-PS group versus no AD-SP after 8 years of evolution.
| Psychosis % (n) | OR (CI95%) | p | |
|---|---|---|---|
| Total | 72.1 (49/68) | - | - |
| Serotonin | 0.003 | ||
| >7.74 | 100.0 (16/16) | invaluable | |
| 0–7.73 | 63.5 (33/52) | 1 | |
| Gender | 0.690 | ||
| Men | 75.0 (18/24) | 1.3 (0.4–3.9) | |
| Woman | 70.5 (31/44) | 1 | |
| Age | |||
| <68 years | 76.9 (10/13) | 1 | |
| 68–72 years | 73.3 (11/15) | 0.8 (0.1–4.6) | 0.827 |
| 73–77 years | 78.3 (18/23) | 1.1 (0.2–5.5) | 0.926 |
| >77 years | 58.8 (10/17) | 0.4 (0.1–2.1) | 0.303 |
| APOE genotype | 0.483 | ||
| 3 | 86.7 (13/15) | invaluable | |
| 4 | 100.0 (14/14) | 1 | |
| MMSE | 0.154 | ||
| 24–27 | 78.9 (30/38) | 2.2 (0.7–6.4) | |
| >27 | 63.3 (19/30) | 1 | |
| Barthel Schelle | 0.664 | ||
| 90–95 | 85.7 (6/7) | 2.5 (0.3–22.4) | |
| 100 | 70.5 (43/61) | 1 | |
| Lawton-Brody Schelle | 0.844 | ||
| 0–5 | 71.7 (43/60) | 0.8 (0.2–4.6) | |
| >5 | 75.0 (6/8) | 1 | |
| NPI | 0.001 | ||
| ≥4 | 86.0 (37/43) | 6.7 (2.1–21.4) | |
| 0–4 | 48.0 (12/25) | 1 | |
| UPDRS III | 0.009 | ||
| >1 | 100.0 (14/14) | invaluable | |
| 0 | 64.8 (35/54) | 1 |
MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; UPDRS III: Unified Parkinson’s disease rating scale; OR (CI95%): Odds ratio (confidence interval 95%).
References
- Korf, A.; Liu, C.; Ginghina, C.; Shi, M.; Zhang, J. Alzheimer’s Disease Neuroimaging Initiative. α-Synuclein in CSF of Alzheimer’s Disease and Mild Cognitive Impairment. J. Alzheimers Dis. 2013, 36, 679–688. [Google Scholar]
- Toledo, J.B.; Korff, A.; Shaw, L.M.; Trojanowski, J.Q.; Zhang, J. CSF α-Synuclein Improves Diagnostic and Prognostic Performance of CSF Tau and Aβ in Alzheimer’s Disease. Acta Neuropathol. 2013, 126, 683–697. [Google Scholar]
- Mackin, R.S.; Insel, P.; Zhang, J.; Mohlenhoff, B.; Galasko, D.; Weiner, M.; Mattsson, N. CSF α-Synuclein and Lewy Body-Like Symptoms in Normal Controls, Mild Cognitive Impairment and Alzheimer’s Disease. J. Alzheimers Dis. 2014, 43, 1007–1016. [Google Scholar] [CrossRef]
- Slaets, S.; Van Mechelen, E.; Bastard, N.; Le Decraemer, H.; Van Dijck, M.; Martin, J.J.; De Deyn, P.P.; Engelborghs, S. Increased CSF α-Synuclein Levels in Alzheimer’s Disease: Correlation with Tau Levels. Alzheimers Dement. 2014, 10, S290–S298. [Google Scholar]
- Chiasserini, D.; Biscetti, L.; Eusebi, P. Differential Role of CSF Fatty Acid Binding Protein 3, α-Synuclein and Alzheimer’s Disease Core Biomarkers in Lewy Body Disorders and Alzheimer’s Dementia. Alzheimers Res. Ther. 2017, 9, 52. [Google Scholar] [PubMed]
- Shi, M.; Tang, L.; Toledo, J.B. CSF α-Synuclein Contributes to the Differential Diagnosis of Alzheimer’s Disease. Alzheimers Dement. 2018, 14, 1052–1062. [Google Scholar] [PubMed]
- Bousiges, O.; Philippi, N.; Lavaux, T.; Pierre, A.; Lachmann, I.; Blanc, F. Total alpha-synuclein assay in the Cerebro-Spinal-Fluid is of interest in the differential diagnosis between Alzheimer’s disease and dementia with Lewy bodies from the prodromal stage. BMC Neurol. 2020. Epub ahead of printing. [Google Scholar] [CrossRef]
- García-Ayllón, M.S.; Monge-Argilés, J.A.; Monge-García, V.; Navarrete-Rueda, F.; Cortés-Gómez, M.A.; Sánchez-Payá, J.; Manzanares-Robles, J.; Gasparini-Berenguer, R.; Leiva-Santana, C.; Sáez-Valero, J. Measurement of CSF α-Synuclein Improves Early Differential Diagnosis of Mild Cognitive Impairment Due to Alzheimer’s Disease. J. Neurochem. 2019, 150, 218–230. [Google Scholar] [CrossRef]
- Jack, C.R.; Bennett, D.A.; Blennow, K.; Carrillo, M.C.; Dunn, B.; Haeberlein, S.B.; Holtzman, D.M.; Jagust, W.; Jessen, F.; Karlawish, J.; et al. NIA-AA Research Framework: Toward a Biological Definition of Alzheimer’s Disease. Alzheimers Dement. 2018, 14, 535–562. [Google Scholar] [CrossRef]
- Pérez-Romero, A.; González-Garrido, S. The Importance of Behavioural and Psychological Symptoms in Alzheimer’s Disease. Neurologia 2018, 33, 378–384. [Google Scholar]
- Murray, P.S.; Kumar, S.; DeMichele-Sweet, M.A.A.; Sweet, R.A. Psychosis in Alzheimer’s Disease. Biol. Psychiatry 2014, 75, 542–552. [Google Scholar] [CrossRef] [PubMed]
- Cummings, J. New Approaches to Symptomatic Treatments for Alzheimer’s Disease. Mol. Neurodegener. 2021, 16, 2. [Google Scholar] [CrossRef] [PubMed]
- Monge-García, S.; García-Ayllón, M.S.; Sánchez-Payá, J.; Gasparini-Berenguer, R.; Cortés-Gómez, M.Á.; Sáez-Valero, J.; Monge-Argilés, J.A. Validity of CSF α-Synuclein to Predict Psychosis in Prodromal Alzheimer’s Disease. Front. Neurol. 2023, 14, 1124145. [Google Scholar] [CrossRef]
- Ballard, C.; Kales, H.C.; Lyketsos, C.; Aarsland, D.; Creese, B.; Mills, R.; Williams, H.; Sweet, R.A. Psychosis in Alzheimer’s Disease. Curr. Neurol. Neurosci. Rep. 2020, 20, 57. [Google Scholar] [CrossRef]
- Chakraborty, S.; Lennon, J.C.; Malkaram, S.A.; Zeng, Y.; Fisher, D.W.; Dong, H. Serotonergic System, Cognition, and BPSD in Alzheimer’s Disease. Neurosci. Lett. 2019, 704, 36–44. [Google Scholar] [CrossRef]
- Tang, L.; Wang, Y.; Chen, Y.; Chen, L.; Zheng, S.; Bao, M.; Xiang, J.; Luo, H.; Li, J.; Li, Y. The Association between 5HT2A T102C and Behavioral and Psychological Symptoms of Dementia in Alzheimer’s Disease: A Meta-Analysis. BioMed Res. Int. 2017, 2017, 5320135. [Google Scholar] [CrossRef]
- Scarmeas, N.; Brandt, J.; Albert, M.; Hadjigeorgiou, G.; Papadimitriou, A.; Dubois, B.; Sarazin, M.; Devanand, D.; Honig, L.; Marder, K.; et al. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch. Neurol. 2005, 62, 1601–1608. [Google Scholar] [CrossRef]
- Collerton, D.; Taylor, J.P. Advances in the treatment of visual hallucinations in neurodegenerative diseases. Future Neurol. 2013, 8, 433–444. [Google Scholar] [CrossRef]
- Garcia-Alloza, M.; Gil-Bea, F.J.; Diez-Ariza, M.; Chen, C.H.; Francis, P.T.; Lasheras, B.; Ramirez, M.J. Cholinergic-Serotonergic Imbalance Contributes to Cognitive and Behavioral Symptoms in Alzheimer´s Disease. Neuropsychologia 2005, 43, 442–449. [Google Scholar] [CrossRef]
- Cummings, J.; Cortez-Pinto, L.; Cruz, M.; Fischer, C.E.; Gerritsen, D.L.; Grossberg, G.T.; Hwang, T.J.; Ismail, Z.; Jeste, D.V.; Koopmans, R.; et al. Criteria for Psychosis in Major and Mild Neurocognitive Disorders: International Psychogeriatric Association Consensus Clinical and Research Definition. Am. J. Geriatr. Psychiatry 2020, 28, 1256–1269. [Google Scholar] [CrossRef] [PubMed]
- Ballard, C.; Youakim, J.M.; Coate, B.; Stankovic, S. Pimavanserin in Alzheimer’s Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms. J. Prev. Alzheimers Dis. 2018, 6, 27–33. [Google Scholar] [CrossRef]
- Chen, Y.; Sun, J.; Yang, Z.; Bi, H. Efficacy and Safety of Negative Allosteric Modulators of 5-HT2A Receptors in the Treatment of Alzheimer’s Disease Psychosis: A Systematic Review and Meta-Analysis. Adv. Clin. Exp. Med. 2023, 32, 1089–1098. [Google Scholar] [CrossRef] [PubMed]
- Cummings, J.L.; Devanand, D.P.; Stahl, S.M. Dementia-related psychosis and the potential role for pimavanserin. CNS Spectr. 2022, 27, 7–15. [Google Scholar] [CrossRef] [PubMed]
- Helzner, E.P.; Scarmeas, N.; Cosentino, S.; Tang, M.X.; Schupf, N.; Stern, Y. Survival in Alzheimer Disease: A Multiethnic, Population-Based Study of Incident Cases. Neurology 2008, 71, 1489–1495. [Google Scholar] [CrossRef] [PubMed]
Figure 1.
Distribution of patients across groups and control group in February 2024.
Figure 2.
Displays the empirical cumulative distribution functions of CSF serotonin levels (A), NPI scores (B) and UPDRS-III scores (C) in the two clinical groups: individuals who developed PS during follow-up (blue line) and those who remained asymptomatic (green line) in February 2024.
Figure 2.
Displays the empirical cumulative distribution functions of CSF serotonin levels (A), NPI scores (B) and UPDRS-III scores (C) in the two clinical groups: individuals who developed PS during follow-up (blue line) and those who remained asymptomatic (green line) in February 2024.
Figure 3.
Hazard Ratios (HRs) and adjusted Hazard Ratios (HR1) are shown in the right panel, reflecting the effect of each variable after controlling for potential confounders. MMSE: Mini mental State Examination; NPI: Neuropsychiatric Inventory; UPDRS-III: Unified Parkinson’s Disease Rating Scale III. BARTHEL: Barthel’s Scale; LAWTON-BRODY: Lawton Instrumental Activities of daily living scale.
Figure 3.
Hazard Ratios (HRs) and adjusted Hazard Ratios (HR1) are shown in the right panel, reflecting the effect of each variable after controlling for potential confounders. MMSE: Mini mental State Examination; NPI: Neuropsychiatric Inventory; UPDRS-III: Unified Parkinson’s Disease Rating Scale III. BARTHEL: Barthel’s Scale; LAWTON-BRODY: Lawton Instrumental Activities of daily living scale.
Figure 4.
Receiver Operating Characteristics (ROC) analysis of CSF 5-HT concentrations. CSF 5-HT levels of 4.89 ng/mL demonstrated an area under the curve of 0.78 for distinguishing Alzheimer’s disease patients based on the presence of psychotic symptoms.
Figure 4.
Receiver Operating Characteristics (ROC) analysis of CSF 5-HT concentrations. CSF 5-HT levels of 4.89 ng/mL demonstrated an area under the curve of 0.78 for distinguishing Alzheimer’s disease patients based on the presence of psychotic symptoms.
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MDPI and ACS Style
Monge-García, V.; Pérez-González, R.; Monge-García, S.; Gasparini-Berenguer, R.; Sánchez-Payá, J.; Silva-Afonso, R.d.F.; Monge-Argilés, J.-A. Elevated CSF Serotonin in Prodromal Alzheimer’s Disease Patients Developing Psychosis. J. Dement. Alzheimer's Dis. 2026, 3, 14. https://doi.org/10.3390/jdad3010014
AMA Style
Monge-García V, Pérez-González R, Monge-García S, Gasparini-Berenguer R, Sánchez-Payá J, Silva-Afonso RdF, Monge-Argilés J-A. Elevated CSF Serotonin in Prodromal Alzheimer’s Disease Patients Developing Psychosis. Journal of Dementia and Alzheimer's Disease. 2026; 3(1):14. https://doi.org/10.3390/jdad3010014
Chicago/Turabian StyleMonge-García, Victoria, Rocío Pérez-González, Sonia Monge-García, Ruth Gasparini-Berenguer, José Sánchez-Payá, Raissa de Fátima Silva-Afonso, and José-Antonio Monge-Argilés. 2026. "Elevated CSF Serotonin in Prodromal Alzheimer’s Disease Patients Developing Psychosis" Journal of Dementia and Alzheimer's Disease 3, no. 1: 14. https://doi.org/10.3390/jdad3010014
APA StyleMonge-García, V., Pérez-González, R., Monge-García, S., Gasparini-Berenguer, R., Sánchez-Payá, J., Silva-Afonso, R. d. F., & Monge-Argilés, J.-A. (2026). Elevated CSF Serotonin in Prodromal Alzheimer’s Disease Patients Developing Psychosis. Journal of Dementia and Alzheimer's Disease, 3(1), 14. https://doi.org/10.3390/jdad3010014
