Background: Neurocognitive disorders (NCDs) have a variable decline in cognitive function, while loneliness was associated with cognitive impairment and increased dementia risk. In the present study, we examined the associations of loneliness with functional and cognitive status in patients with minor (mild cognitive impairment) and major NCDs (dementia). Methods: We diagnosed mild NCD (n = 42) and major NCD (n = 164) through DSM-5 criteria on 206 participants aged > 65 years using the UCLA 3-Item Loneliness Scale (UCLA-3) to evaluate loneliness, the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales to measure functional status, and Mini-Mental State Examination (MMSE) to assess cognitive functions. Results: In a multivariate regression model, the effect of loneliness on cognitive functions was negative in major (β = −1.05, p < 0.0001) and minor NCD (β = −0.06, p < 0.01). In the fully adjusted multivariate regression model (sex–age–education–multimorbidity–depressive symptoms–antidementia drug treatment), the effect of loneliness remained negative for major NCD and became positive for minor NCD (β = 0.09, p < 0.001). The effect of loneliness on IADL (β = −0.26, p < 0.0001) and ADL (β = −0.24, p < 0.001) showed a negative effect for major NCD across the different models, while for minor NCD, the effect was positive (IADL: β = 0.26, p < 0.0001; ADL: β = 0.05, p = 0.01). Minor NCD displayed different levels of MMSE (β = 6.68, p < 0.001) but not ADL or IADL, compared to major NCD for the same levels of loneliness. MANOVA pill test suggested a statistically significant and different interactive effect of loneliness on functional and cognitive variables between minor and major NCDs. Conclusions: We confirmed the relationships between loneliness and cognitive and functional status in major NCD, observing a novel trend in minor NCD.

Background: Neurocognitive disorders (NCDs) have a variable decline in cognitive function, while loneliness was associated with cognitive impairment and increased dementia risk. In the present study, we examined the associations of loneliness with functional and cognitive status in patients with minor (mild cognitive impairment) and major NCDs (dementia). Methods: We diagnosed mild NCD (n=42) and major NCD (n=164) through DSM-5 criteria on 206 participants aged>65 years using the UCLA 3-Item Loneliness Scale (UCLA-3) to evaluate loneliness, the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales to measure functional status, and Mini-Mental State Examination (MMSE) to assess cognitive functions. Results: In a multivariate regression model, the effect of loneliness on cognitive functions was negative in major (=-1.05-p<.0001) and minor NCD (=-0.06-p<.01). In the fully-adjusted multivariate regression model (sex-age-education-multimorbidity-depressive symptoms-antidementia drug treatment), the effect of loneliness remained negative for major NCD and became positive for minor NCD (=0.09-p<.001). The effect of loneliness on IADL (=-0.26-p<.0001) and ADL (=-0.24-p<.001) showed a negative effect for major NCD across the different models, while for minor NCD, the effect was positive (IADL:=0.26-p<.0001-ADL:=0.05-p=0.01). Minor NCD displayed different levels of MMSE (=6.68-p<.001), but not ADL or IADL, compared to major NCD for the same levels of loneliness. MANOVA pill’s test suggested a statistically significant and different interactive effect of loneliness on functional and cognitive variables between minor and major NCDs. Conclusions: We confirmed the relationships between loneliness and cognitive and functional status in major NCD, observing a novel trend in minor NCD.

Background: Neuropsychiatric symptoms (NPSs) are among the most clinically disruptive manifestations of major neurocognitive disorder (MND) and major contributors to caregiver distress. However, the differential contribution of specific neuropsychiatric domains to caregiver burden and sleep quality has remained insufficiently characterized. Methods: This single-center retrospective observational study included 164 patient–caregiver dyads. Patients were diagnosed with MND according to DSM-5 criteria. NPS were assessed using the Neuropsychiatric Inventory (NPI-Q). Caregiver burden and sleep quality were evaluated using the 12-item Zarit Burden Interview (ZBI-12) and the Pittsburgh Sleep Quality Index (PSQI), respectively. Beta and logistic regression models were applied to investigate associations between NPS severity and caregiver outcomes after adjustment for cognitive and functional status. Additional analyses explored the relative contribution of individual NPI-Q subdomains. Results: Greater overall NPS severity was significantly associated with both increased caregiver burden (β = 0.163, p < 0.001) and altered caregiver sleep quality (OR = 1.32, 95% CI: 1.12–1.59, p = 0.002). Clinically significant sleep disturbances (PSQI > 5) were observed in 61.6% of caregivers. Among NPS, delusions showed the strongest association with caregiver burden (β = 0.329, p < 0.001), followed by depressive symptoms (β = 0.156, p = 0.004) and irritability (β = 0.147, p = 0.005); furthermore, sleep and night-time behavior disorders emerged as the strongest contributors to altered caregiver sleep quality (p < 0.001). Conclusions: Greater NPS severity may be associated with increased caregiver burden and poorer sleep quality in caregivers of patients with MND. Different NPSs appear to be differentially associated with caregiver outcomes, despite the lack of caregiver-level covariates, supporting the need for multidimensional and caregiver-centered approaches in dementia care. Given the exploratory nature of these analyses, these findings should be interpreted as descriptive rather than confirmatory.

Late-life depression (LLD) is increasingly recognized as a complex multisystem disorder associated with accelerated biological aging, impaired physiological resilience, frailty, and an increased risk of cognitive decline and dementia. Although growing evidence supports the close relationship between depression, frailty, and neurodegeneration, the molecular mechanisms underlying this continuum remain incompletely understood. In particular, conventional clinical and imaging biomarkers capture established disease but provide limited insight into the systemic biological processes that precede neurodegeneration. Proteomics has emerged as a powerful systems biology approach capable of characterizing the dynamic molecular networks involved in aging, neuropsychiatric disorders, and neurodegenerative diseases. Recent advances in high-throughput mass spectrometry have identified alterations in proteins associated with chronic inflammation, complement activation, mitochondrial dysfunction, oxidative stress, lipid metabolism, synaptic integrity, neurotrophic signaling, and cellular senescence across LLD, frailty, cognitive impairment, and Alzheimer's disease (AD). These convergent proteomic signatures suggest that these conditions may share common biological pathways reflecting progressive loss of physiological resilience rather than independent pathological entities. In this review, we examine the current evidence supporting shared proteomic mechanisms linking LLD, frailty, cognitive frailty (CF), and neurodegeneration. We discuss the potential integration of large-scale proteomic profiling with established AD biomarkers within the AT(N) framework to improve biological characterization, early risk stratification, and prediction of cognitive decline. Particular emphasis is placed on CF as a transitional and potentially modifiable phenotype in which systemic molecular dysregulation precedes overt neurodegeneration. By integrating evidence from geroscience, neuropsychiatry, and proteomics, we propose that proteomic profiling can redefine LLD and frailty as manifestations of a common biological vulnerability continuum. This systems-level perspective may facilitate the identification of individuals at high risk for dementia, support the development of multimodal biomarker panels, and advance precision neuropsychiatry through earlier diagnosis and personalized preventive interventions.

Background: Language impairment is a core feature of Major Neurocognitive Disorder (MND), yet the domain-specific relationship between language functioning and everyday functional status remains insufficiently characterized. Methods: We conducted a retrospective observational study in 125 older adults diagnosed with MND according to DSM-5 criteria with mild-to-moderate cognitive impairment measured with Mini-Mental State Examination (MMSE). Language performance was assessed using semantic, phonemic verbal fluency and confrontation naming. Functional status was evaluated using basic (BADL) and instrumental activities of daily living (IADL). Ordinal logistic regression models examined associations between language domains and functional outcomes, adjusting for global cognitive status (MMSE), demographic variables, multimorbidity, and depressive symptoms. Model fit was evaluated using the Akaike Information Criterion. Results: Semantic fluency emerged as the best-performing predictor of BADL across all hierarchical models, remaining statistically significant after full adjustment for MMSE and clinical covariates (β ≈ 0.60, p < 0.05). Phonemic fluency showed the most robust association with IADL, with a stable effect across models, reaching a trend toward statistical significance in the fully adjusted analyses (β ≈ 0.22–0.27, p = 0.069). Naming ability did not influence functional outcomes. All observed associations persisted after controlling for MMSE, demographic variables, multimorbidity, and depressive symptoms. Conclusions: Language abilities showed differential associations across language domains with functional status in this sample of patients with MND. Semantic fluency was associated with basic self-care, while phonemic fluency showed a trend toward association with instrumental daily activities. These relationships remained observable after adjustment for global cognitive impairment, suggesting verbal fluency as a potentially sensitive marker of functional vulnerability.