Song C, Zhan W, Tang JY, Liu ZH, Huang YP. Serum adiponectin and cognitive function in Alzheimer’s disease with comorbid depression. World J Psychiatry 2026; 16(7): 118148 [DOI: 10.5498/wjp.118148]
Corresponding Author of This Article
Yong-Pan Huang, Dean, School of Medicine, Changsha Social Work College, No. 22 Xiangzhang Road, Yuhua District, Changsha 410004, Hunan Province, China. songchong0731@163.com
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Clinical Neurology
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Song C, Zhan W, Tang JY, Liu ZH, Huang YP. Serum adiponectin and cognitive function in Alzheimer’s disease with comorbid depression. World J Psychiatry 2026; 16(7): 118148 [DOI: 10.5498/wjp.118148]
Co-corresponding authors: Jia-Yu Tang and Yong-Pan Huang.
Author contributions: Song C, Zhan W, Tang JY and Liu ZH contributed to research design, data collection, data analysis, and paper writing; Huang YP was responsible for research design, funding application, data analysis, reviewing and editing, communication coordination, ethical review, copyright and licensing, and follow-up. Song C and Zhan W contributed equally to this work as co-first authors. We designate two co-corresponding authors because both Huang YP and Tang JY made substantial and equal contributions to this study, sharing critical responsibilities in conceptualization, methodology design, data interpretation, manuscript drafting, and revision. Huang YP, based at Changsha Social Work College, led the research design, funding acquisition, and overall project coordination, while Tang JY, from Brain Hospital of Hunan Province, oversaw the clinical data collection, patient recruitment, and cognitive assessments. Given their complementary expertise in pharmacology and neurology, and their joint leadership throughout all stages of the research-from inception to final submission-it is appropriate to recognize them as co-corresponding authors. This arrangement ensures comprehensive correspondence regarding both the academic oversight and clinical aspects of the work, reflecting their equally significant intellectual and supervisory roles in this collaborative project.
AI contribution statement: We use DeepL to assist in polishing the language of the manuscript. However, we did not use AI to write the content of the manuscript. The entire content (abstract, introduction, materials and methods, results, discussion, and conclusion) of this manuscript, with the exception of some parts, was not generated by AI. The entire main content of this article was written by the author. The design of the study and the interpretation of the results were completed by the author. All the pictures were created by the author and no AI technology was used.
Supported by Education Department of Hunan Province, No. 25C1704; and Natural Science Foundation of Hunan Province, No. 2023JJ60263.
Institutional review board statement: The research was reviewed and approved by The Brain Hospital of Hunan Province.
Informed consent statement: All research participants or their legal guardians provided written informed consent prior to study registration.
Conflict-of-interest statement: No conflict of interest is associated with this work.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: No other data available.
Corresponding author: Yong-Pan Huang, Dean, School of Medicine, Changsha Social Work College, No. 22 Xiangzhang Road, Yuhua District, Changsha 410004, Hunan Province, China. songchong0731@163.com
Received: January 27, 2026 Revised: February 12, 2026 Accepted: March 20, 2026 Published online: July 19, 2026 Processing time: 154 Days and 3.2 Hours
Abstract
BACKGROUND
Depression is a highly prevalent comorbidity in Alzheimer’s disease (AD), exacerbating cognitive decline and worsening prognosis. Adiponectin (APN), an adipokine with anti-inflammatory and neuroprotective properties, has been implicated in both conditions, yet its role in the comorbid state remains unclear. We hypothesized that serum APN levels would be significantly reduced in these patients and would independently correlate with the severity of cognitive impairment.
AIM
To investigate the association between serum APN levels and cognitive function in AD patients with comorbid depression.
METHODS
This observational study enrolled 60 AD patients with depression and 60 healthy controls from a hospital neurology department. The observation group was subclassified into mild, moderate, and severe groups using the Clinical Dementia Rating Scale. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Serum APN levels were determined via ELISA, and metabolic/inflammatory markers were also assessed. Data were analyzed using t-tests, ANOVA, Pearson correlation, and multiple linear regression.
RESULTS
In the observation group serum APN levels (6.67 ± 1.99 μg/mL) and MoCA/MMSE scores were considerably lower than in control group (12.53 ± 2.87 μg/mL; all P < 0.001). Within the observation group, APN levels and cognitive scores decreased progressively with worsening disease severity (all P < 0.001). Serum APN was positively associated with MoCA (r = 0.781, P < 0.001) and MMSE scores (r = 0.643, P < 0.001). After adjusting for metabolic/inflammatory factors, APN remained an independent predictor of MoCA scores (t = 8.009, P < 0.001).
CONCLUSION
Serum APN levels are markedly reduced in AD patients with depression and closely correlate with impaired cognition. APN may represent a potential biomarker for assessing cognitive status in this population.
Core Tip: This study demonstrates a significant reduction in serum adiponectin (APN) levels in patients with Alzheimer’s disease (AD) complicated by depression, which progressively declines with worsening disease severity and independently correlates with cognitive impairment. These findings highlight APN as a promising peripheral biomarker for cognitive assessment in AD-depression comorbidity, offering potential pathways for novel therapeutic strategies and more precise clinical monitoring.
Citation: Song C, Zhan W, Tang JY, Liu ZH, Huang YP. Serum adiponectin and cognitive function in Alzheimer’s disease with comorbid depression. World J Psychiatry 2026; 16(7): 118148
Alzheimer’s disease (AD) is the most frequent neurodegenerative condition and the world's leading cause of dementia. It is increasingly recognized as one of the most medically, economically, and socially challenging diseases of the 21st century[1]. As the global population continues to age at an accelerated pace, the incidence of AD has risen consistently, positioning it as a critical public health threat that profoundly compromises the physical, mental, and emotional well-being of older adults, while severely diminishing their overall quality of life[2]. Current epidemiological projections paint a concerning picture: By 2050, the total number of individuals living with AD and other dementias is anticipated to soar to approximately 152 million globally, underscoring the escalating scale of this health crisis[3]. Among the complex array of neuropsychiatric manifestations in AD, depression stands out as one of the most frequent and clinically significant comorbidities, affecting an estimated 20% to 45% of AD patients-a rate substantially higher than that observed in the general elderly population[4]. Notably, even mild depressive features have been associated with accelerated cognitive deterioration and progressive brain atrophy in this vulnerable group, suggesting a synergistic detrimental effect on neurocognitive integrity[5]. This interplay between neurodegenerative progression and affective disturbance not only exacerbates disease burden but also complicates clinical management and caregiver support. Given these interlinked pathophysiological and clinical realities, a deeper investigation into the association between AD and co-occurring depression is imperative. Understanding the bidirectional mechanisms-how AD pathophysiology may predispose to depression, and how depressive states may in turn worsen AD progression-can inform more integrated and personalized treatment approaches. Such insights carry substantial clinical relevance, offering potential pathways to slow cognitive and functional decline, alleviate behavioral and psychological symptoms, and ultimately improve the overall long-term outcomes and life quality for patients navigating the dual challenge of AD and depression.
Adiponectin (APN) is a multifunctional cytokine predominantly produced by fatty tissue, recognized for its significant anti-inflammatory, anti-apoptotic, and metabolic regulatory properties, and can influence the central nervous system by crossing the blood-brain barrier[6]. Clinically, the relationship between APN levels and cognitively function presents a complex and often contradictory picture. Certain cross-sectional studies have indicated that serum APN concentrations are notably lower in patients with AD compared to individuals with mild cognitive impairment or healthy controls, and these levels show a strong positive association with Mini-Mental State Examination (MMSE) scores. These discoveries indicate that reduced APN levels may function as a biochemical indicator reflecting the severity of AD pathology[7]. On the other hand, contrasting research reports elevated APN levels in AD populations, which may indicate a physiological compensatory mechanism or a state of resistance within downstream signaling pathways under chronic disease conditions[8]. These discrepancies highlight that APN expression is likely influenced by a range of factors, including the specific stage of neurodegenerative progression and the presence of metabolic comorbidities, underscoring the need for more nuanced, longitudinal investigations to clarify its role in cognitive health and disease.
Based on this understanding, the present study utilized a case-control design to systematically compare APN levels and cognitive performance between patients diagnosed with AD complicated by depression and demographically matched healthy controls. By analyzing the relationship between serum APN concentrations and cognitive assessment scores, and further investigating the independent association of APN with cognitive function through statistical modeling, this research aims to provide new theoretical insights into the pathophysiology of comorbid AD and depression, thereby offering potential foundations for improved disease monitoring and future targeted interventions in this vulnerable patient population.
MATERIALS AND METHODS
General information
Sixty patients diagnosed with AD complicated by depression in the Department of Neurology at our hospital between January 2022 and November 2023 were included as the observation group. For comparison, 60 age- and gender-matched healthy volunteers who attended our hospital for routine physical examinations during the same period were recruited as the control group to ensure baseline comparability in demographic and clinical characteristics.
Inclusion criteria: (1) Meeting the definition of AD in the diagnostic criteria for AD and diagnosed with AD after admission to the hospital by imaging questionnaire[9]; (2) Hamilton Depression Scale-24 items score ≥ 8[10]; (3) Age ≥ 65 years old; and (4) Complete clinical data.
Exclusion criteria: (1) Severe systemic diseases such as hepatic and renal insufficiency, diabetic ketoacidosis, malignant tumors, etc.; (2) Other types of dementia (e.g., dementia with vascular causes, Lewy body dementia, etc.); (3) Other severe psychiatric illnesses (e.g., schizophrenia, bipolar disorder); (4) The use of medications that may affect the APN level or mood in the last month, such as glucocorticoids, antidepressants etc.; and (5) Those who are unable to cooperate in completing the scale assessment.
Scale assessment
AD severity assessment: AD severity was determined via the Clinical Dementia Rating Scale (CDR). The CDR evaluates six domains: Memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. A global CDR score is derived from these domain ratings, with severity classified as follows: CDR = 0 (no dementia), 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). In this study, the observation group was categorized into mild (CDR = 1, n = 22), moderate (CDR = 2, n = 24), and severe (CDR = 3, n = 14) subgroups based on the global CDR score[11].
Assessment of cognitive function: Utilizing the Montreal Cognitive Assessment Scale (MoCA, Chinese version)[12] and MMSE[13] were used, which were assessed by uniformly trained neurology fellows. The MoCA assesses multiple domains (visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, orientation) with a total score of 30. A score of ≤ 26 is indicative of cognitive impairment, with an additional point awarded for individuals with ≤ 12 years of education. The MMSE evaluates orientation, registration, attention and calculation, recall, and language, also totaling 30 points. Lower scores indicate more severe cognitive impairment, with common cut-offs being ≥ 27 for normal, 21-26 for mild, 10-20 for moderate, and < 10 for severe impairment.
Serum marker testing
All participants in the study must be fasting for 8 to 12 hours prior to specimen collection. On the morning of testing, a trained nurse collected approximately 5 mL of venous blood from the antecubital vein using EDTA anticoagulant tubes. The blood samples were then left undisturbed at room temperature for 2 hours to facilitate clotting. Subsequently, they were centrifuged at 2000 rpm for 20 minutes to separate the serum from cellular components. The resulting serum was carefully aliquoted into pre-labeled cryogenic EP tubes and immediately stored at -80 °C to preserve biochemical stability until analysis. To ensure consistency and minimize batch variation, all samples were processed collectively after the completion of recruitment and sample collection.
Serum APN levels were measured utilizing an ELISA test kit purchased from Shanghai Enzyme-Linked Bio-Technology Co., Ltd. The coefficients of variation for both within-assay and between-assay replicates were below 10%. Procedures strictly followed the kit instructions, with serum APN levels calculated from absorbance measurements against a standard curve. Concurrently, metabolic parameters including fasting plasma glycemia (FPG), total cholesterin (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured. High-sensitivity C-reactive protein (hs-CRP) levels were assessed using an immunoturbidimetric assay.
Statistical analysis
Data were analyzed by using SPSS 21.0 software. For continuously distributed variables meeting the assumption of normal distribution, results are presented as mean ± SD, and group comparisons employed independent samples t-test; Comparisons between groups were conducted with one-way ANOVA, with post hoc comparisons made by LSD test. The median (interquartile range) [M (P25, P75)] was used to represent non-normally distributed quantitative data, and the intergroup comparisons were conducted using nonparametric Mann-Whitney U test. Categorical variables were presented as n (%), and intergroup comparisons were made by χ2 test or Fisher’s exact test. Correlation analysis was performed using Pearson’s correlation method. Multiple linear stepwise regression analysis was employed to explore the independent link between serum APN levels and cognitive scores. A P < 0.05 was considered to be of statistical significance.
RESULTS
Comparison of baseline characteristics between the two groups
Table 1 indicated that there were no statistically significant differences in baseline characteristics such as age, gender, education level, body mass index, and comorbidities between the two groups (P > 0.05), ensuring comparability. However, the observation group exhibited significant metabolic and inflammatory dysregulation, with markedly elevated levels of FPG, TC, TG, LDL-C, and hs-CRP, and significantly lower levels of HDL-C (all P < 0.05).
Table 1 Comparison of baseline characteristics between the two groups, n (%).
Comparison of APN levels and cognitive function scores between the two groups
Table 2 showed that cognitive function (MoCA, MMSE) in the observation group was markedly poorer than in the control group (P < 0.001). Correspondingly, the key indicator, serum APN level, was significantly lower in the observation group (6.67 ± 1.99 μg/mL) than in the control group (12.53 ± 2.87 μg/mL, P < 0.001).
Table 2 Comparison of adiponectin levels and cognitive function scores between the two groups.
Comparison of APN levels and cognitive function scores among observation group patients with different disease severities
Table 3 demonstrates that within the observation group, patients with varying disease severity showed significant differences in serum APN levels, MoCA scores, and MMSE scores (all P < 0.001). APN levels and cognitive scores decreased progressively from the mild to the severe group.
Table 3 Comparison of adiponectin levels and cognitive function scores among observation group patients with different disease severities, mean ± SD.
Correlation analysis between serum APN levels and cognitive function scores in the observation group
Pearson correlation analysis in Table 4 revealed that serum APN levels were significantly positively correlated with both MoCA scores (r = 0.781, P < 0.001) and MMSE scores (r = 0.643, P < 0.001).
Table 4 Correlation analysis between serum adiponectin levels and cognitive function scores in the observation group.
Multiple linear regression analysis in the observation group
Multiple linear regression analysis in Table 5 further indicated that, after adjusting for FPG, TC, TG, HDL-C, LDL-C, and hs-CRP, serum APN level (t = 8.009, P < 0.001) remained an independent influencing factor of the total MoCA score.
Table 5 Multiple linear regression analysis in the observation group.
AD is one of the most common forms of dementia among the elderly worldwide, accounting for 60% to 80% of all cases[14]. It is marked by a progressive deterioration in cognition, functional, and behavioral abilities, typically beginning with memory loss for recent events[15]. Currently, the global numbers of patients with AD dementia, early-stage AD, and subclinical AD are approximately 32 million, 69 million, and 315 million individuals, respectively. Collectively, these groups constitute 416 million people within the AD cohort, which makes up 22% of the population aged 50 and older[16]. By 2050, the affected population is projected to rise to approximately 152 million, with developing regions experiencing the largest increase[17]. In developed countries, approximately one in ten older adults (aged 65 and above) is affected in the earlier stages of AD, while more than one in three individuals aged 85 and above are likely to exhibit the later symptoms and indicators of the disease[18]. It is noteworthy that population-based studies in European countries have shown the proportion of AD patients rising from 0.6% in the 65-69 age group to 22.2% among those aged 90 and above, further confirming the gradual upward trend in the global prevalence of AD[19]. Despite the central symptoms of AD being impairments in memory and various cognitive functions, psychoneuropsychiatric features like anxious and depressed mood are frequently recognized throughout the clinical progression. As the most common neuropsychiatric comorbidity in AD, the incidence of anxious disorders varies from 9.4% (in the prediagnostic stage) to 39% (from milder to severe progression), while the incidence of depressive disorders in patients with milder to moderate AD ranges between 14.8% and 40%[20]. Based on widely recognized diagnostic criteria, the estimated prevalence of depression among AD patients ranges from 20% to 45%[4]. This comorbid “AD-depression” condition is not merely a simple overlap of symptoms but rather a bidirectional interaction mechanism involving “neurodegeneration-neuroinflammation-emotional dysregulation” leading to dual impairment of cognitively and daily functioning. On one hand, β-amyloid (Aβ) deposition and hyperphosphorylated tau protein in AD patients damage brain regions involved in mood-regulating brain regions such as the hippocampal and prefrontal cortex, increasing the risk of depression[21]. On the other hand, hyperactivity of the hypothalamic-pituitary-adrenal axis during depressive states exacerbates neuroinflammatory responses, promotes Aβ aggregation and neuronal apoptosis, and accelerates the progression of AD[22]. Clinical data indicate that patients with AD complicated by depression exhibit significantly impaired cognitive function compared to those with AD alone[23], and their quality of life is markedly reduced[24]. This condition also affects activities of daily living, increases the risk of bodily harm, and may accelerate nursing home placement and mortality among AD patients[25]. This severe clinical reality highlights the harm of comorbid AD and depression as a “high-risk subtype” and underscores the urgent need to identify biological markers for precise disease assessment and prognosis prediction, thereby providing a basis for optimizing treatment strategies.
Against this research backdrop, APN has garnered significant attention due to its pleiotropic biological functions. As a cytokine primarily secreted by adipocytes, its classical functions are centered in the field of metabolic regulation, such as enhancing insulin sensitivity and suppressing vascular endothelial inflammation[26]. However, recent neuroscientific research has shown that APN can cross the blood-brain barrier, express its receptors in the central nervous system, regulate neural activity across multiple brain regions, and activate a series of downstream signaling pathways, thereby demonstrating potent anti-inflammatory, antioxidant, anti-apoptotic, as well as neurotrophic and neuroprotective properties[27]. Studies indicate that as a therapeutic candidate, APN can alleviate inflammatory responses by promoting M2 polarization of microglia through the AdipoR1/APPL1/AMPK/PPAR γ signaling pathway, thereby alleviating inflammatory responses and ultimately mitigating hemorrhage-induced inflammatory brain injury[28]. In pathological models of depression, decreased APN levels due to chronic stress are associated with reduced hippocampal neurogenesis and depressive-like behaviors. Research has shown that the decline in APN levels and the downregulation of its specific receptor AdipoR1 in the hippocampus impair synaptic structure and function of hippocampal neurons (including dendritic spine loss and reductions in excitatory/inhibitory synapses), thereby inducing core depressive symptoms such as anhedonia and behavioral despair[29,30]. Some studies have noted abnormal changes in APN levels in patients with AD or depression alone[31,32], yet its change pattern in comorbid conditions and its dynamic relationship with cognitive function remain insufficiently elucidated.
The present study extends these findings by demonstrating that serum APN is markedly reduced in AD patients with comorbid depression, declines progressively with increasing dementia severity, and remains an independent predictor of cognitive impairment after adjusting for metabolic and inflammatory confounders. This suggests that APN’s association with cognition may operate, at least in part, through pathways beyond systemic metabolism-potentially via direct neuroprotective effects in the brain.
Although this study has clarified the expression characteristics and clinical significance of APN in patients with AD comorbid with depression, several important limitations should be acknowledged and addressed in future investigations. First, the relatively modest sample size of 60 cases per group may introduce sampling bias, limiting the generality of the study findings. Furthermore, the cross-sectional design precludes definitive conclusions about causality-it remains unclear whether decreased APN levels precede and contribute to cognitive impairment or whether cognitive decline and emotional disturbances together drive APN downregulation. Clarifying this temporal and mechanistic relationship will require prospective, multicenter, large-scale longitudinal cohort studies to track dynamic changes in APN over time and assess its predictive value for cognitive trajectory. Second, this study measured APN only in peripheral serum and did not evaluate cerebrospinal fluid APN concentrations or the expression of key cerebral APN receptors (AdipoR1/R2). Since patients with AD comorbid depression may exhibit altered blood-brain barrier permeability, peripheral APN levels may not fully reflect central APN concentrations. Future studies should simultaneously measure APN levels in peripheral blood and cerebrospinal fluid to analyze their correlation and differences in association with cognitive function, while also examining the expression of AdipoR1/R2 receptors in the brain to determine whether APN signaling pathways are impaired. Moreover, this study did not analyze different APN subtypes (e.g., low-, medium-, and high-molecular-weight multimers), which may differentially affect cognitive function. Further subtype-specific investigations are needed to identify the specific APN isoforms responsible for neuroprotective effects. Finally, this study has not explored the effect of interventions on APN status and cognitively impaired individuals, lacking evidence from a clinical intervention perspective.
CONCLUSION
In conclusion, APN levels are significantly reduced in patients with AD comorbid with depression, progressively decline with increasing disease severity, and show a significant positive correlation with cognitive function scores, serving as an independent influencing factor of cognitive function. This finding not only deepens the understanding of the pathological mechanisms underlying AD with comorbid depression but also provides new insights for clinical practice-serum APN may potentially be used as a biomarker for assessing cognitive function in such patients, offering an objective basis for disease screening, severity evaluation, and prognosis prediction. Moreover, it identifies a novel therapeutic target for this high-risk subtype, with the potential to improve cognitive function and emotional states by upregulating APN levels, ultimately enhancing the prognosis of these patients.
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P-Reviewer: Arias de la Torre J, MD, Associate Professor, United Kingdom; Zavaliangos-Petropulu A, PhD, United States S-Editor: Qu XL L-Editor: A P-Editor: Zhao YQ
