@article {pmid41327893,
year = {2026},
author = {Akçimen, F and Daida, K and Lange, LM and Moller, A and Miano-Burkhardt, A and Malik, L and Paquette, K and Alvarez Jerez, P and Mingle, J and Baker, B and Meredith, M and Kouam, C and Jarreau, P and Markham, A and Anderson, J and Jain, M and Chaisson, M and Cookson, M and Casey, B and Iwaki, H and Bandres-Ciga, S and Saffie-Awad, P and Nalls, MA and Fang, ZH and Singleton, AB and Blauwendraat, C and Billingsley, KJ},
title = {Long-read sequencing identifies FGF14 repeat expansions in Parkinson's disease.},
journal = {Brain : a journal of neurology},
volume = {149},
number = {5},
pages = {1514-1521},
doi = {10.1093/brain/awaf456},
pmid = {41327893},
issn = {1460-2156},
support = {/AG/NIA NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; Z01-AG000949//National Institutes of Health, Department of Health and Human Services/ ; 1ZIANS003154//National Institutes of Health, Department of Health and Human Services/ ; //NIH HPC Biowulf cluster/ ; },
mesh = {Humans ; *Parkinson Disease/genetics/diagnostic imaging ; Male ; Female ; Aged ; *Fibroblast Growth Factors/genetics ; Middle Aged ; *Trinucleotide Repeat Expansion/genetics ; Whole Genome Sequencing ; alpha-Synuclein/metabolism ; Cohort Studies ; Aged, 80 and over ; },
abstract = {Pathogenic GAA repeat expansions in FGF14 are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease. Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1 can contribute to atypical or familial forms of Parkinson's disease, we investigated whether FGF14 expansions might play a similar role. Using long-read whole-genome sequencing, we analysed 411 individuals with Parkinson's disease and 197 neurologically healthy controls from the Parkinson's Progression Markers Initiative (PPMI) cohort, together with 1429 additional controls from the National Institutes of Health (NIH) Center for Alzheimer's Disease and Related Dementias (CARD) initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations. We identified pathogenic FGF14 GAA repeat expansions in five individuals with Parkinson's disease and one control subject. All five individuals fit the clinical criteria of Parkinson's disease and showed typical patterns of neurodegeneration on DaTSCAN imaging; α-synuclein aggregation was confirmed by a positive seeding assay among four individuals with available data. These findings broaden the phenotypic spectrum of FGF14 repeat-associated disease and suggest a rare, previously unrecognized genetic contributor to Parkinson's disease. To our knowledge, this is the first report implicating FGF14 in Parkinson's disease and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.},
}

Humans
*Parkinson Disease/genetics/diagnostic imaging
Male
Female
Aged
*Fibroblast Growth Factors/genetics
Middle Aged
*Trinucleotide Repeat Expansion/genetics
Whole Genome Sequencing
alpha-Synuclein/metabolism
Cohort Studies
Aged, 80 and over

@article {pmid42082123,
year = {2026},
author = {Fan, YH and Fan, KS and Lin, TL},
title = {Reduced dementia risk in middle-aged and older atopic dermatitis patients treated with dupilumab: A target trial emulation.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106796},
doi = {10.1016/j.bbi.2026.106796},
pmid = {42082123},
issn = {1090-2139},
abstract = {BACKGROUND: Middle-aged and older adults with atopic dermatitis (AD) are at increased risk of dementia, possibly driven by chronic inflammation and involving IL-4 and IL-13 pathways. Whether treatment with dupilumab, an IL-4/IL-13 inhibitor, influences subsequent dementia risk in this population remains unclear.

METHODS: This target trial emulation study utilized the TriNetX database. Patients aged ≥ 50 years with AD were identified and divided into two groups: those newly prescribed dupilumab and those newly prescribed conventional systemic agents without dupilumab exposure. Propensity score matching (1:1) was performed based on age, sex, race, and comorbidities. Dementia risk was assessed using Cox regression.

RESULTS: After matching, each group included 10,039 patients (∼52% female; mean age, 63 years; 63% White). The 5-year cumulative incidence of dementia was lower among dupilumab users than controls (2.37% vs 3.33%; P = 0.001). Dupilumab use was associated with a reduced risk of all-cause dementia (HR 0.68; 95% CI, 0.54-0.86), with similar reductions observed across dementia subtypes, including secondary (HR 0.69; 95% CI, 0.48-0.99), unspecified (HR 0.70; 95% CI, 0.53-0.93), and Alzheimer's dementia (HR 0.61; 95% CI, 0.40-0.93). Subgroup and sensitivity analyses showed consistent results, with control outcome analyses supporting the robustness of the findings. In a validation analysis of middle-aged and older asthma patients, dupilumab users likewise had a lower dementia risk than omalizumab users (HR 0.68; 95% CI, 0.47-0.98).

CONCLUSIONS: Dupilumab use was associated with a reduced risk of dementia in middle-aged and older adults with AD compared with conventional systemic agents.},
}

@article {pmid42082387,
year = {2026},
author = {Alpert, JM and Rothberg, MB and Paasche-Orlow, MK and Hashmi, AZ and Perez-Protto, S and Fox, J and Criswell, V and Wittenberg, E},
title = {A communication phenotype for varying information needs among caregivers of persons with dementia.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag091},
pmid = {42082387},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Informal caregivers of persons with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) have limited knowledge of the disease, yet they have immense responsibility, such as medication administration, managing symptoms, assisting with activities of daily living, and making end-of-life decisions. Our objective was to explore information seeking among informal caregivers to learn about their information needs.

RESEARCH DESIGN AND METHODS: We interviewed informal caregivers of persons with AD/ADRD who passed away in the last two years. Interviews occurred from July 2024 to June 2025 in a large academic health system. We analyzed information needs of AD/ADRD caregivers using an adapted version of the Four States of Information Needs conceptual framework. We used a deductive-inductive approach, beginning with the existing framework, and then refining it with inductive observations.

RESULTS: Twenty-seven informal caregivers were interviewed (median age 65 years; 77.8% female; 81.5% white; care provided for a median of 5 years; 63.0% were the patient's child). Four phenotypes were revealed: 1) Proactive Caregivers, who were assertive communicators and motivated to seek information in advance, 2) Activated Caregivers, who had less knowledge than Proactive Caregivers, but communicated with staff and took preemptive measures, 3) Responsive Caregivers, who were overwhelmed and rarely communicated their needs to clinical staff, and 4) Reflective Caregivers, who identified information gaps, but did not always attempt to rectify them.

DISCUSSION AND IMPLICATIONS: The needs of informal caregivers vary. Potentially, clinicians can recognize caregivers' phenotypes and adapt the support they provide to improve the caregiver experience.},
}

@article {pmid42082519,
year = {2026},
author = {Wang, J and Mao, Y and Liu, X and Hao, W and , },
title = {Learning patient-specific spatial biomarker dynamics via operator learning for Alzheimer's disease progression.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00719-x},
pmid = {42082519},
issn = {2056-7189},
support = {1R35GM146894/GM/NIGMS NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized future biomarker states remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.},
}

@article {pmid42082780,
year = {2026},
author = {Khalili, E and Sodaei, F and Noroozian, M and Sheldrick-Michel, TM and Vafaee, MS},
title = {Structural MRI in frontotemporal dementia and Alzheimer's disease: stage-dependent atrophy patterns.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42082780},
issn = {1435-1463},
abstract = {Differentiating Alzheimer's disease (AD) from frontotemporal dementia (FTD) remains a major clinical challenge, particularly in early disease stages when phenotypic overlap is common and in later stages when cortical degeneration becomes widespread. Structural magnetic resonance imaging (MRI) provides a widely available, non-invasive framework for assessing region-specific brain atrophy patterns associated with these disorders. This narrative review synthesizes current evidence on MRI-based approaches for distinguishing FTD from AD across disease stages. FTD, particularly the behavioral variant, is characterized by early and prominent degeneration of frontal and anterior temporal networks, frequently with hemispheric asymmetry and early behavioral change, including apathy as a core feature. In contrast, AD typically demonstrates a posterior-predominant pattern, with medial temporal and temporoparietal atrophy reflecting a posterior-to-anterior trajectory, while frontal involvement emerges later except in atypical variants. Quantitative MRI techniques, including voxel-based morphometry, cortical thickness analysis, and asymmetry indices, together with validated visual rating scales, enhance the detection of these spatial patterns. Fluid-attenuated inversion recovery imaging supports interpretation by identifying vascular burden, and complementary biomarkers, including FDG-PET, cerebrospinal fluid, and blood-based markers, provide molecular and functional context in diagnostically ambiguous cases. The diagnostic specificity of frontal atrophy is greatest in early stages and decreases as AD and FTD converge anatomically in moderate to advanced disease. Accurate differential diagnosis, therefore, requires a stage-aware, integrative framework that combines structural MRI with longitudinal clinical assessment, neuropsychological profiling, and biomarker information. Structural MRI remains the cornerstone of differentiation, with regional atrophy patterns interpreted within a broader clinical and biological context rather than in isolation.},
}

@article {pmid42082800,
year = {2026},
author = {Nazli, D and Poyraz, YK and Can, K and Ipekgil, D and Cakmak, N and Turhanlar-Sahin, E and Hacoglu, S and Erdost, HA and Iyilikci, L and Ozhan, G},
title = {Dexmedetomidine Exerts Multi-level Effects to Ameliorate Alzheimer's Disease Pathology in the Adult Zebrafish Brain.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42082800},
issn = {1559-1182},
mesh = {Animals ; Zebrafish ; *Dexmedetomidine/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/genetics ; *Brain/pathology/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Aging/pathology/drug effects ; Behavior, Animal/drug effects ; Peptide Fragments ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.},
}

Animals
Zebrafish
*Dexmedetomidine/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/genetics
*Brain/pathology/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Aging/pathology/drug effects
Behavior, Animal/drug effects
Peptide Fragments

@article {pmid42082802,
year = {2026},
author = {Motieiyan, E and Motahari, R and Aliabadi, A and Khaksar, S and Abdolmaleki, S},
title = {Cobalt complexes in biology and medicine: enzymatic functions, pharmacological applications, and health challenges.},
journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry},
volume = {},
number = {},
pages = {},
pmid = {42082802},
issn = {1432-1327},
abstract = {Cobalt is an essential trace element in biochemistry that plays a crucial role in the structure and function of several important biomolecules. In this review, vitamin B12 is discussed as one of the best-known examples in this area. Various forms of this vitamin, including methylcobalamin and adenosylcobalamin, play a crucial role in metabolic reactions in mammals and prokaryotes. It also discusses cobalt-containing enzymes that are essential for various biological processes. These enzymes are B12-dependent enzymes, which are well studied, and cobalt-containing enzymes, which are less well known, such as methionine aminopeptidase, nitrile hydratase, glucose isomerase, and prolidase. In addition to the significant role of cobalt complexes in biochemistry, these complexes are considered potent anticancer agents that can exert their antiproliferative effects through the production of ROS, cell cycle arrest, MMP breakdown, and induction of apoptosis in cancer cells. Cobalt complexes are also being explained here for their antimicrobial properties against a variety of pathogens, including bacteria, fungi, and viruses. Furthermore, examples of these complexes are presented as promising agents for the suppression of AD, which could be effective by binding to Aβ-peptides and preventing their aggregation, which is a central feature of the pathogenesis of AD, or by combating the oxidative damage associated with the disease, or even by interfering with the enzyme activities associated with this disease. Finally, the challenges related to the toxicity of cobalt and its compounds in medicine are discussed, and chelation therapy is considered an effective treatment for cobalt poisoning.},
}

@article {pmid42082835,
year = {2026},
author = {Zheng, X and Chen, P and Li, D and Li, W and Liao, J and Zhang, M},
title = {Lamotrigine Improves Spatial Learning and Attenuates AD-Related Pathology in APP/PS1 Mice, with Possible Involvement of the cAMP/PKA/CREB Pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42082835},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Lamotrigine/pharmacology/therapeutic use ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Spatial Learning/drug effects ; Mice, Transgenic ; Mice ; Presenilin-1/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; Male ; Brain/drug effects/metabolism/pathology ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by impaired spatial learning functions, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. Antiepileptic drugs such as lamotrigine have shown promise in improving brain functions in AD, but the underlying mechanisms remain unclear. This study aimed to evaluate the therapeutic effects of lamotrigine in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and elucidate the underlying molecular mechanisms using integrated transcriptomic and metabolomic analyses. APP/PS1 mice were treated with lamotrigine from 3 months of age, and spatial learning performance was assessed using the Morris water maze test. Histological and molecular changes were evaluated through hematoxylin and eosin staining, Western blotting, ELISA, and immunohistochemistry. High-throughput RNA sequencing and untargeted metabolomics were performed to explore differentially expressed genes, metabolites, and enriched signaling pathways. Western blot validation and pharmacological inhibition were used to verify pathway involvement. Lamotrigine treatment significantly improved spatial learning performance, ameliorated neuronal degeneration, and decreased Aβ1 levels and tau phosphorylation in the brains of APP/PS1 mice. Inflammatory markers and glial activation were also markedly suppressed. Multi-omics analysis revealed alterations in key pathways related to synaptic plasticity, lipid metabolism, and autophagy. Notably, both omics data and protein validation highlighted the cAMP/PKA/CREB pathway as a potentially relevant pathway. Co-administration of the PKA inhibitor H89 abolished lamotrigine-induced upregulation of p-CREB and BDNF, supporting the involvement of this pathway. Lamotrigine improves spatial learning and attenuates AD-related pathology in APP/PS1 mice, possibly through modulation of the cAMP/PKA/CREB signaling pathway, highlighting its potential as a candidate for further investigation.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Lamotrigine/pharmacology/therapeutic use
Cyclic AMP-Dependent Protein Kinases/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
*Spatial Learning/drug effects
Mice, Transgenic
Mice
Presenilin-1/genetics
Cyclic AMP Response Element-Binding Protein/metabolism
Signal Transduction/drug effects
Cyclic AMP/metabolism
Male
Brain/drug effects/metabolism/pathology
Maze Learning/drug effects

@article {pmid42082911,
year = {2026},
author = {Müller, T and Hornung, R and Szymczak, S and Buchner, H},
title = {ShadowVIMP: permutation-based multiple testing-controlled variable selection.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-026-06412-4},
pmid = {42082911},
issn = {1471-2105},
support = {DFG-Einzelförderung HO 6422/1-3//German Science Foundation/ ; },
abstract = {BACKGROUND: Identifying relevant biomarkers is critical in clinical research and precision medicine, particularly when analysing high-dimensional data. Random forests (RFs) are promising for such settings due to their flexibility, ease of use, and their ability to handle data sets with more variables than samples. RFs assess the importance of each variable in predicting the outcome using variable importance (VIMP) scores. However, since the distribution of VIMP scores is intricate, standard statistical testing and multiple testing adjustments for variable selection are challenging.

METHODS: We propose shadowVIMP, a novel method for multiple testing-controlled variable selection, based on an approach similar to permutation testing. It generates permuted counterparts for each variable and compares their VIMPs with those of the original variables over multiple iterations to calculate p-values. Unlike conventional permutation testing, shadowVIMP preserves the correlation structure between variables, mitigating biases caused by the over-selection of correlated variables in RFs. We evaluated shadowVIMP against three competing RF variable selection approaches using simulation designs previously employed in studies considering VIMPs and variable selection for RFs. These designs included high- and low-dimensional data, as well as correlated and categorical variables. For illustration, we also applied the method to a real-world example on Alzheimer's disease.

CONCLUSIONS: Our results showed that, compared to competing approaches, shadowVIMP offers advantages in high-dimensional settings, improving sensitivity while enabling multiple testing-adjusted results. Additionally, it demonstrated robustness against VIMP biases induced by correlated and categorical variables when using permutation-based VIMP. The method can be used to annotate standard VIMP plots, visually presenting selected variable sets based on different types of multiple testing adjustments and significance levels. Overall, shadowVIMP is a promising approach for providing multiple testing-adjusted variable selection while explicitly addressing known biases of RF's permutation-based VIMP measure. The shadowVIMP method is implemented in an R package shadowVIMP, which is available on CRAN.},
}

@article {pmid42082924,
year = {2026},
author = {Salian, V and Wang, Z and Curran, G and Podulso, JF and Kandimalla, KK},
title = {Estimation of Various Physiological Parameters Affecting Amyloid Plaque Distribution of a Novel MRI Contrast Agent in the Brain of Alzheimer's Disease Transgenic Mice.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c01565},
pmid = {42082924},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides as plaques in the brain parenchyma and as deposits in the cerebral vasculature. Early detection of amyloid plaques and deposits is imperative for diagnosing AD before the onset of cognitive decline. Magnetic resonance (MR) imaging using Gd (III)-based agents for contrast enhancement and plaque targeting provides a promising avenue. However, there remains a challenge due to the limited permeability of these contrast agents across the blood-brain barrier (BBB), which restricts its delivery. Furthermore, clearance mechanisms in the brain also reduce retention of contrast agents. To identify mechanisms that limit the success of contrast agents, we investigated the pharmacokinetics and the brain distribution of contrast agent, Gd[N-4ab/Q-4ab]Aβ30, using AD transgenic mouse models and compartmental modeling. Our results demonstrate that the contrast agent is internalized by parenchymal cells, which limits its availability to bind to extracellular plaques. Sensitivity analysis conducted on the compartmental model identified systemic clearance and plasma-to-brain influx as key parameters that limit the delivery of the contrast agent to the brain. The analysis also highlights the BBB as a formidable barrier for delivery and the importance of improving BBB permeability to increase the accumulation of the contrast agent in the brain. Furthermore, model simulations revealed that glymphatic drainage contributes to the poor retention and rapid elimination of the contrast agent from the brain. By elucidating the role of these biological processes and parameters, this study contributes to understanding factors limiting contrast agent efficacy in amyloid plaque imaging in the AD brain. These findings also reveal important targets for optimizing contrast agent design to improve its brain delivery.},
}

@article {pmid42082960,
year = {2026},
author = {Liu, S and Zhu, J and Zhong, H and Zhou, D and Long, Q and Zhang, Z and Yang, X and Wu, Q and Cheng, C and Wu, J and Luu, HN and Wang, J and Zhao, B and Wu, C and Deng, Y and Wu, L},
title = {Investigating causal associations among inflammatory proteins, blood metabolites, and Alzheimer's disease risk.},
journal = {BMC psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12888-026-08136-4},
pmid = {42082960},
issn = {1471-244X},
abstract = {Alzheimer's disease (AD) is a prevalent degenerative neurological disorder with limited treatment options. Prior studies reported specific metabolites and inflammatory proteins to be related to AD risk. However, the intricate relationship between inflammatory proteins, blood metabolites, and AD risk in European population remains unclear. Genetic instruments for 1,091 metabolites and 736 inflammatory proteins were derived from two recent comprehensive genome-wide association studies. Univariable Mendelian Randomization was employed to assess potential causal effects of metabolites on AD risk, potential effects of inflammatory proteins on metabolites, and effects of inflammatory proteins on AD risk. Multivariable MR (MVMR) was further applied to disentangle direct effects of proteins and metabolites on AD. Twelve metabolites were identified to be associated with AD risk, and 226 inflammatory proteins demonstrated likely to be causal effects on these 12 metabolites. Further examining the associations between such inflammatory proteins and AD risk revealed 22 associations for which the effect directions from inflammatory proteins to metabolites, from metabolites to AD risk, and from inflammatory proteins to AD risk were aligned, suggesting inflammatory protein - metabolite - AD risk pathway. MVMR further highlighted four trios in which the effect directions were consistent with the UVMR results, supporting a metabolite‑mediated pattern. This large‑scale genetic analysis highlights specific metabolites as direct contributors to AD risk and suggests that certain inflammatory proteins may influence AD primarily through downstream metabolic pathways. Our findings offer potential novel therapeutic targets for AD intervention.},
}

@article {pmid42083037,
year = {2026},
author = {López-López, V and Iniesta, G and Galán-Ganga, M and Expósito-Coca, A and Durán-Laforet, V and Bhojwani-Cabrera, AM and Navarrón, CM and Guillot-Fernández, M and Venero, JL and Sánchez-Mut, JV and Barco, A and Giralt, A and López-Atalaya, JP},
title = {Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03840-0},
pmid = {42083037},
issn = {1742-2094},
abstract = {Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.},
}

@article {pmid42083115,
year = {2026},
author = {Jiang, X and O'Bryant, SE and Rissman, RA and Johnson, LA and Braskie, MN and Yaffe, K and , },
title = {Multimorbidity and Associations with Cognition and Alzheimer's Disease Biomarkers.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78238},
pmid = {42083115},
issn = {1531-8249},
abstract = {OBJECTIVE: Multimorbidity, the coexistence of 2 or more chronic conditions, has been linked to cognitive aging and Alzheimer's disease (AD) and AD-related dementias, yet the mechanisms remain unclear. We aimed to examine the associations of multimorbidity with cognition and biomarkers across multiple mechanistic pathways.

METHODS: We cross-sectionally analyzed 3,808 dementia-free participants (mean age 64.9 ± 8.5 years, 62% female) from the Health and Aging Brain Study: Health Disparities. Multimorbidity burden was assessed using a latent construct derived from chronic conditions identified through objective measures, medical history, and self-report. A latent factor score for cognition was estimated using confirmatory factor analysis and neuropsychological tests. Using linear and logistic regression, we examined the associations of multimorbidity burden with biomarkers of AD (positron emission tomography [PET] amyloid, plasma β-amyloid 42/40, and phosphorylated tau [p-tau] measures), neurodegeneration (cortical thickness, hippocampal volume, and plasma neurofilament light and total tau), and cerebral small vessel disease (SVD) (magnetic resonance imaging white matter hyperintensities, cerebral microbleeds, and lacunes).

RESULTS: Greater multimorbidity burden was associated with worse cognition and biomarkers of AD (PET amyloid standardized uptake value ratios and positivity, p-tau181, and p-tau217), neurodegeneration (neurofilament light, total tau, cortical thickness, and hippocampal volume), and SVD (white matter hyperintensity volume and presence of lacune and cerebral microbleeds).

INTERPRETATION: Among dementia-free individuals, higher multimorbidity burden was associated with biomarkers for greater AD pathology, neurodegeneration, and SVD. These findings support a more holistic approach to managing chronic disease burden, which has the potential to reduce overall pathophysiological burden and delay cognitive decline. ANN NEUROL 2026.},
}

@article {pmid42083360,
year = {2026},
author = {Pandey, H and Kaur, A and Khan, J and Sharma, A},
title = {Nanomedicine for Alzheimer's Disease: Diagnostic and Therapeutic Progress.},
journal = {MicroRNA (Shariqah, United Arab Emirates)},
volume = {},
number = {},
pages = {},
doi = {10.2174/0122115366427696260203074113},
pmid = {42083360},
issn = {2211-5374},
abstract = {The complex nature of the pathophysiology and limited treatment options of AD make it a huge challenge in healthcare. The recent developments in nanotechnology have given fresh hope for diagnosing and treating AD, which could serve as a way out of the existing problems. This review dwells on the role of nanotechnology in AD and its applications at its early stages through the development of nanosensors and boost imaging methods. Additionally, nanotechnology-driven therapeutic strategies are being investigated with nanoparticle-based drug delivery systems that aim to target the blood-brain barrier, among others. Current research innovations, clinical trials, and prospects highlight the transformative potential of nanotechnology in reshaping AD management. Ethical issues related to applying nanomedicine in neurodegenerative diseases, as well as fears about nanoparticles, are carefully analyzed herein. Finally, this review concludes with a synthesis of how nanotechnology has affected Alzheimer's Disease (AD) while emphasizing emerging trends and future directions toward advancing research on Alzheimer's Disease (AD). This comprehensive overview underscores the pivotal role of nanotechnology in revolutionizing AD prognosis and therapy, paving the way for personalized and effective treatment strategies.},
}

@article {pmid42083372,
year = {2026},
author = {Yoshida, H and Inoue, T and Suzuki, S and Tomata, Y},
title = {Sodium-to-Potassium Ratio and Alzheimer's Disease: A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050472115260421093303},
pmid = {42083372},
issn = {1875-5828},
abstract = {INTRODUCTION: A higher urinary sodium-to-potassium (Na/K) ratio has been associated with increased risk of hypertension and cardiovascular diseases, which are known risk factors for Alzheimer's Disease (AD). Mendelian Randomization (MR), which uses genetic variants as instrumental variables to infer causality while reducing confounding and reverse causation, was applied to investigate whether the urinary Na/K ratio is causally associated with AD risk.

METHODS: A two-sample MR study was conducted using 31 single-nucleotide polymorphisms associated with urinary Na/K ratio as instrumental variables. The primary analysis employed Genome- Wide Association Study (GWAS) summary statistics for AD (n=85,934 individuals, including ADby- proxy). For sensitivity analysis, GWAS data specific to clinically diagnosed late-onset AD (n=21,982 individuals) were analyzed.

RESULTS: Genetically predicted urinary Na/K ratio was not statistically significantly associated with AD risk in the primary analysis; odds ratio (OR per 1 mol/mol increase) = 1.02, 95% confidence interval (CI): 0.77-1.36. In the sensitivity analysis using clinically diagnosed late-onset AD, the point estimate was higher (OR = 1.49, 95% CI: 0.99-2.24), although the association was not statistically significant.

DISCUSSION: Although no statistically significant causal association was observed, the study's findings may be consistent with previous observational studies linking higher sodium intake or a higher urine Na/K ratio to poorer cognitive performance. However, the sensitivity analysis suggested a possible association that warrants further investigation in larger MR studies using clinically confirmed AD datasets. As all data were derived from individuals of European ancestry, generalizability to other populations may be limited.

CONCLUSION: This MR study did not provide clear evidence supporting a causal association between urinary Na/K ratio and AD risk.},
}

@article {pmid42083373,
year = {2026},
author = {Zhang, Y and Tong, S and Chen, Y and Li, C and Yao, Y and Tang, S and Shang, Y},
title = {An Inverse Association Between the Composite Dietary Antioxidant Index and Alzheimer's Disease: Evidence from an NHANES-Based Cross-Sectional Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050462427260407045906},
pmid = {42083373},
issn = {1875-5828},
abstract = {INTRODUCTION: The relationship between the dietary Complex Antioxidant Index (CDAI) and Alzheimer's Disease (AD) is not clear. Our study is to investigate the relationship between CDAI and the risk of AD in general adults.

METHODS: This study included 116876 participants from the National Health and Nutrition Survey (NHANES). CDAI was calculated based on the intake of six dietary antioxidants. We used multivariate logistic regression to examine the relationship between CDAI and AD prevalence, and used restricted cubic splines to examine the nonlinear association.

RESULTS: The study showed that in the multivariate logistic regression model with fully adjusted confounding variables, the odds ratio (OR) of CDAI and AD was 0.9983 (95% confidence interval: 0.9969,0.9998; P=0.024). In addition, restricted cubic spline analysis revealed a linear correlation (P for non-linearity = 0.097).

DISCUSSION: This cross-sectional study reveals a linear negative association between the CDAI and AD prevalence in U.S. adults, with vitamin E, carotenoids, and selenium showing independent protective effects. These findings align with the hypothesis that dietary antioxidants may mitigate oxidative stress-related neurodegeneration. However, due to the cross-sectional design, causal inference is not possible, and reverse causation cannot be excluded. The modest effect size and reliance on self-reported dietary data necessitate cautious interpretation. These hypothesis-generating findings underscore the need for prospective cohort studies to confirm whether antioxidant-rich diets could serve as a primary prevention strategy for AD.

CONCLUSION: This cross-sectional study found a negative linear association between CDAI and AD prevalence in US adults. These hypothesis-generating findings require confirmation in prospective cohort studies.},
}

@article {pmid42083380,
year = {2026},
author = {Mai, X and Chen, J and Yong, K and Chen, Y and Wen, H and Sun, M and Yu, H and Xiong, K and Yu, L},
title = {A Dual-Functional Two-Photon PLIM Probe Based on Ruthenium(II) Complex: Sequence Selectivity and Aβ Aggregation Monitoring.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c08075},
pmid = {42083380},
issn = {1520-6882},
abstract = {A key pathological feature of Alzheimer's disease (AD) is β-amyloid (Aβ) plaque formation from abnormal peptide aggregation. In addition to full-length Aβ1-42, various N/C-truncated Aβ fragments exist in the human brain and are found to be associated with AD etiology. However, the precise toxic Aβ species, aggregation states, and neurotoxic mechanisms remain unclear, highlighting the urgent need for probes with sequence selectivity and real-time aggregation monitoring capability─functions lacking in reported Aβ probes. Herein, we present Ru-dmpip, a two-photon phosphorescence lifetime imaging microscopy (PLIM) probe synthesized by conjugating a hydrophilic ruthenium complex and a hydrophobic ThT moiety. Ru-dmpip exhibits high specificity for AβX-42 peptides (Aβ1-42/Aβ11-42), with 7.4/3.7-fold higher affinity than Aβ1-40, and can bind all AβX-42 aggregated states (monomers/oligomers/fibrils), inducing sensitive phosphorescence intensity and lifetime changes (the lifetime increased from 436 to approximately 900 ns). It can visualize Aβ1-42 aggregation at the single-fiber level, enable in vitro cellular imaging, and specifically identify plaques formed by Aβ1-42 in APP-PS1 transgenic mouse brain sections. Its ultralong excited-state lifetime can effectively mitigate interference from background, allowing clear observation of loose small oligomers surrounding plaques─species that are barely detectable via conventional spectral imaging. Binding mechanism studies show Ru-dmpip interacts with Aβ1-42 via hydrogen bonding with the C-terminus and electrostatic attraction with the N-terminus. As the first two-photon PLIM probe integrating sequence selectivity and aggregation monitoring, Ru-dmpip provides a valuable tool for AD pathological research and inspires the design of sequence-specific Aβ sensors.},
}

@article {pmid42083474,
year = {2026},
author = {Aktar, BSK and Karaküçük-İyidoğan, A and Yılmaz, GT and Oruç-Emre, EE and Sıcak, Y and Bakırdöven, A and Turgut-Solak, ZD and Öztürk, M},
title = {Therapeutic potential of sulfonate-based hydrazide hydrazones in neurodegenerative diseases: SAR insights and molecular modeling studies.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/17568919.2026.2665469},
pmid = {42083474},
issn = {1756-8927},
abstract = {AIMS: Cholinesterase inhibitors represent an important therapeutic strategy in combating Alzheimer's disease.

MATERIAL AND METHODS: The novel 4-((2-(substitutedbenzoyl)hydrazinylidene)methyl)phenyl 2/3/4-(trifluoromethoxy)benzene-1-sulfonates (1-40) were synthesized from the reaction of 4-Formylphenyl-2/3/4-trifluoromethoxybenzene-1-sulfonate with various substituted benzoic acid hydrazides. The structures of all hybrid molecules were conclusively elucidated by elemental analysis and some spectroscopic techniques (IR, NMR, MS). These compounds were evaluated for their cholinesterase (AChE and BChE) inhibitory activities.

RESULTS: Compound 33, carrying a nitro group at the 4-position of the phenyl ring among the series, exhibited the highest inhibitory activity, showing IC50 values of 8.11 ± 0.52 µM for AChE and 12.09 ± 0.28 µM for BChE. The molecular docking studies elucidated the interactions of the active compounds with the actives sites of AChE and BChE enzymes were elucidated by molecular docking, supporting their observed anticholinesterase activity.

CONCLUSION: The compatible results of experimental data and in silico analyses demonstrate that these compounds can be considered among effective and potential lead candidates for cholinesterase inhibition targeting AD.},
}

@article {pmid42083542,
year = {2026},
author = {Garg, A and Lavania, K and Parhi, R and Singh, GK and Ahmad, J and Jain, A},
title = {Nanomedicine-Based Approaches for Therapeutic Delivery Across the Blood-Brain Barrier in Neurological Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128412258251127103243},
pmid = {42083542},
issn = {1873-4286},
abstract = {Therapeutic delivery to the Central Nervous System (CNS) is challenging for formulation scientists due to the transfer of therapeutics across the Blood-Brain Barrier (BBB). The BBB consists of a selective semi-permeable anatomical structure of the capillary basement membrane, capillary endothelial cells, pericytes, and astrocytes. It restricts the drug transfer from the blood compartment to the brain tissues. Therefore, the desirable effects of various therapeutics in different CNS disorders (like Alzheimer's disease, schizophrenia, Parkinson's disease, etc.) require the transfer of drugs across the BBB. Hence, various approaches have been explored for deeper penetration of CNS-acting drugs across the BBB. Among various formulation approaches, Drug Delivery Systems (DDS) utilizing colloidal carrier systems are one of the most promising strategies to overcome BBB limitations and achieve brain targeting in different CNS disorders. This review provides a comprehensive discussion of drug delivery challenges across the BBB and technology advancements utilized to achieve improved therapeutic efficacy in different CNS disorders.},
}

@article {pmid42083556,
year = {2026},
author = {Soliani, AG and Muratori, BG and Baptista, JS and Cerutti, SM},
title = {Rodents' episodic-like memory: concepts, ageing, neurodegeneration, future.},
journal = {Translational neuroscience},
volume = {17},
number = {1},
pages = {20250392},
pmid = {42083556},
issn = {2081-3856},
abstract = {Episodic memory (EM), traditionally defined as the conscious recollection of what, where, and when events occurred, was long considered uniquely human due to its reliance on autonoetic awareness. However, behavioural criteria allow memory assessment based on observable features, enabling the study of EM-related processes in non-human species and leading to the concept of episodic-like memory (ELM) in animal models. We review conceptual advances and methodological challenges in ELM research, focusing on rodent models that provide mechanistic insights into neural circuits and molecular pathways supporting memory formation and persistence. Converging evidence highlights the role of hippocampal-prefrontal networks in integrating spatial, temporal, and emotional dimensions of experience. We also discuss data from our laboratory, which provides evidence for cellular and synaptic mechanisms, such as tagging-and-capture, ensemble allocation, and reactivation, that contribute to memory linking and consolidation in the fear-based ELM paradigm. These findings indicate that novelty-dependent recruitment of neuronal ensembles in the dorsal CA1 is impaired during ageing, leading to deficits in the persistence of weak experiences. Additionally, studies using cholinergic hypofunction models, a hallmark of late-onset Alzheimer's disease (LOAD), reveal severe impairments in object recognition, spatial location, and integrated ELM, partially reversed by pharmacological interventions. Collectively, these data emphasise the translational relevance of ELM paradigms for modelling age-related memory decline and neurodegeneration. We also address open questions regarding neuromodulatory influences, sex differences, and the boundary between normal ageing and LOAD. By integrating conceptual, behavioural, and neurobiological perspectives, ELM approaches provide powerful tools for probing memory dynamics and informing therapeutic strategies.},
}

@article {pmid42083572,
year = {2026},
author = {Minhas, AM and Khan, AU and Gul Qazi, N and Nadeem, H and Ali, F},
title = {Pharmacological investigation of oxadiazole derivatives in Alzheimer's disease: Modulation of oxidative stress, neuroinflammation, and iNOS signaling.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {3},
pages = {423-437},
pmid = {42083572},
issn = {2008-3866},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of amyloid-beta (Aβ) aggregates. Aβ peptides alter synaptic function and produce neuroinflammation. The neurotoxic mechanisms are also related to increases in the expression of iNOS (inducible nitric oxide synthase), resulting in further neuronal degeneration and memory impairment.

MATERIALS AND METHODS: In the current study, we assessed the in vivo effect of the 1,3,4-oxadiazole derivative 2-{[5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}-
N-(1,3-benzothiazol-2-yl) acetamide (MA) on spatial memory and inflammatory responses induced by AlCl3 administration in animals.

RESULTS: A notable improvement in memory function was observed in the AlCl3-induced group at 29[th] post-injection, following MA treatment (5, 10, and 20 mg/kg), as indicated by the behavioral analysis. This effect is correlated with decreases in inflammatory markers such as NFKƁ, IL-6/ß1, IFN-γ, TNϜ-α, and NO levels, as well as a reduction in expression of neurodegenerative markers: β-amyloid and p-tau (*P<0.05, **P<0.01, ***P<0.001 vs disease control). The results from our study suggested that MA significantly enhances the levels of glutathione, catalase, and glutathione S-transferase while decreasing the lipid peroxidation (LPO) in comparison to the disease control group, and also improves mitochondrial dysfunction. The effects are further enhanced when MA was used in combination with aminoguanidine (AG), an iNOS inhibitor. Molecular dynamics (MD) simulations, along with protein mRNA expression and iNOS western blotting, further supported the results of in vivo experiments.

CONCLUSION: Our study proposed that MA attenuated the cytokine release, decreased oxidative stress, and iNOS expression, leading to a decrease in neurodegeneration.},
}

@article {pmid42083861,
year = {2026},
author = {Stokes, JE and Pugh, EA and Briggs, E and Lee, G and Leggett, AN and López-Anuarbe, M},
title = {The long arm of divorce and death: Loss, loneliness, and cognition in mid and later life.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394316},
doi = {10.1177/13872877251394316},
pmid = {42083861},
issn = {1875-8908},
abstract = {BackgroundEarly life adversities can have lifelong consequences for health, including for cognitive functioning and Alzheimer's disease and related dementias. Moreover, early-life disadvantages stemming from parental death and divorce have been linked with later life social, mental, and physical well-being outcomes, including social isolation. Therefore, loneliness stands out as an intervenable aspect of well-being that may mediate long-term consequences of early life exposure to parental death and divorce for midlife and older adults' cognitive decline.ObjectiveThe present study aims to determine whether early life exposures to parental death and/or divorce are associated with cognitive functioning in later life, and whether loneliness in midlife mediates such effects.MethodsWe used the 2014-2020 Health and Retirement Study (HRS), 2015 HRS Life History data and longitudinal structural equation modeling to address our research questions.ResultsEarly-life exposure to parental divorce, but not death, was associated with greater loneliness in late midlife and older age, and loneliness predicted more rapid declines to cognitive functioning over time. Mediation was statistically significant (p < 0.05).ConclusionsAlthough racial/ethnic minorities had higher exposure to both parental death and divorce, the effects of parental death and divorce were similar across race/ethnicity. Our results underscore the long-term impacts of parental divorce on well-being and health in adulthood and highlight loneliness as a critical determinant of cognitive declines and disparities in later life.},
}

@article {pmid42083869,
year = {2026},
author = {Alhasan, DM and Hamlin, AM and Meier, HC and Manning, M and Yu, X and Gutierrez, S and Webster, NJ},
title = {Association of childhood residential change with later life memory function and rate of decline in the US Health and Retirement Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394333},
doi = {10.1177/13872877251394333},
pmid = {42083869},
issn = {1875-8908},
abstract = {BackgroundChildhood residential change may affect later-life memory function and risk for Alzheimer's disease. However, few studies have examined this relationship, particularly in minoritized racial/ethnic groups.ObjectiveTo assess the association between number of residences and moving due to financial difficulties in childhood with memory trajectories in later life.MethodsData were from the U.S. Health and Retirement Study. Childhood residential change was measured by the self-reported number of residences before age 16 (0-1, 2, 3, 4 or more; n = 4704). Moving due to financial difficulties before age 16 was categorized as yes versus no (n = 4651). Memory function was measured using composite memory z-scores incorporating direct and proxy assessments from 1996-2016. We utilized mixed-effects linear regression models with subject-specific random slopes and intercepts adjusting for sociodemographic characteristics to estimate associations between residential change and memory overall and by race/ethnicity and parental education.ResultsThe mean age at baseline was 57.6 ± 6.1 years, 78.7% self-identified as non-Hispanic (NH) White, 15.7% as NH-Black, and 5.6% as Other/Unknown. Descriptively, NH-Black adults reported fewer residential changes and had lower baseline memory performance compared to NH-White participants. More frequent residential change in childhood was associated with a slower rate of memory decline but not baseline memory function. Moving due to financial difficulties during childhood was not associated with initial memory levels or rates of memory decline. We did not observe effect modification by race/ethnicity or parental education.ConclusionsResults suggest that childhood residential change may contribute to later life memory trajectories.},
}

@article {pmid42083876,
year = {2026},
author = {Nah, S and Chek, CJ and Montoya, A and Duarte, A and Ryan, LH and Chopik, WJ},
title = {Health behavior mechanisms linking childhood socioeconomic status to Alzheimer's disease and related dementia risk: Exploring gender and racial/ethnic differences.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394317},
doi = {10.1177/13872877251394317},
pmid = {42083876},
issn = {1875-8908},
abstract = {BackgroundLower childhood socioeconomic status (cSES) has been linked to a higher risk of Alzheimer's disease and related dementia (ADRD). Yet, the mechanisms underlying this association remain unclear.ObjectiveThis study examined whether poorer health behaviors in adulthood mediate the association between lower cSES and ADRD risk. We further explored whether the mediating effects of health behaviors vary by gender or race/ethnicity.MethodsData were drawn from 26,631 participants in the Health and Retirement Study (Mage = 61.18 years). Cox proportional hazard models were used to estimate the association between cSES and ADRD risk, as well as the mediating effects of health behaviors, including smoking, heavy drinking, physical activity, and influenza vaccination.ResultsLower cSES was associated with a higher risk of ADRD (hazard ratio = 1.06, [1.02, 1.09]). Lower physical activity mediated this association, accounting for 17.1% of the total effect of cSES on ADRD risk. Subgroup analyses revealed that this mediation was consistent across all gender and racial/ethnic groups, except for foreign-born Hispanics. Smoking mediated the association only for men, explaining 4.2% of the total effect.ConclusionsThese findings suggest that lower cSES may be a risk factor for ADRD partially through lower physical activity across most demographic groups. Interventions promoting physical activity in adulthood could help mitigate the adverse effect of low cSES on ADRD risk. Furthermore, smoking prevention programs may be particularly beneficial for men from lower socioeconomic backgrounds.},
}

@article {pmid42083879,
year = {2026},
author = {Walters, ME and Wong, R and Scambray, KA and Antonucci, TC and Tarraf, W},
title = {The association of adverse childhood experiences and life course relationship quality with late-life cognitive health: Moderation by race/ethnicity and gender.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251394324},
doi = {10.1177/13872877251394324},
pmid = {42083879},
issn = {1875-8908},
abstract = {BackgroundAdverse childhood experiences (ACEs) may increase Alzheimer's disease risk. How particular ACEs differentially relate to cognition and what role life course relationship quality (LCRQ) plays are unclear.ObjectiveAssess how ACEs subgroups relate to cognition and whether associations are impacted by LCRQ.MethodsAdults (ages 50-64 at baseline) from the Health and Retirement Study participated (n = 3225; 2006/2008 = baseline; 2018/2020 = follow-up). Latent class and profile analyses identified ACEs and LCRQ subgroups, respectively. Linear and multinomial logistic regressions related ACEs and LCRQ subgroups to global cognition, cognitive impairment, not dementia (CIND), and dementia at follow-up.ResultsWe identified 4 ACEs (High Adversity, Family Disruptions, Elevated Household Trauma, Low Adversity) and 3 LCRQ ("Strong", "Mixed", "Weak" Ties) classes. Racially/ethnically minoritized adults were more likely to belong to Family Disruptions and Weak Ties classes than White adults. Participants with Family Disruptions (versus Low Adversity) had worse cognition (global: b = -0.78, 95% CI [-1.19;-0.37]; CIND: RRR = 1.50, 95% CI [1.13;1.99]); controlling for LCRQ and sociodemographics attenuated associations. Participants with Weak Ties (versus Strong) had worse cognition (global: b = -2.90, 95% CI [-3.53;-2.26]; CIND: RRR = 3.16, 95% CI [2.12;4.70]; dementia: RRR = 3.64, 95% CI [1.92;6.90]); associations were not explained by covariates.ConclusionsFamily Disruptions negatively impacted cognition, but associations were attenuated by sociodemographics. Assessing life course resources as contributors to resilience may help explain the untenable ACEs-cognition association. However, negative LCRQ was consistently harmful to cognition. Targeting life course social relationships may benefit cognition.},
}

@article {pmid42083945,
year = {2026},
author = {Kumar, D and Walhekar, V and Kasaragod, MS and Kini, S},
title = {Discovery of Novel Quinazoline Thiazole Uredio Analogs as Dual Inhibitors of GSK-3β and CK-1δ as Anti-Alzheimer's Agents: Catching Two Fish with One Net.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266378266251017045841},
pmid = {42083945},
issn = {1873-4294},
abstract = {INTRODUCTION: AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects through the application of structure-based scaffold hopping and molecular hybridization strategies.

METHODS: Molecular docking was carried out on the Glide module, Molecular dynamics simulation of 500 ns was executed employing Desmond, and ADMET prediction was achieved by the QikProp modules of Schrodinger.

RESULTS: Through molecular docking studies targeting the GSK-3β and CK-1δ enzymes, the compounds VDK12 and VDK14 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of -9.9 kcal/mol and -10.1 kcal/mol, respectively. Molecular dynamics simulations further revealed that the VDK12 and VDK14 complexes exhibited stable interactions within the active sites of GSK-3β and CK-1δ throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that VDK1 exhibited an excellent human oral absorption rate of 91.349%, outperforming other compounds in the series.

DISCUSSION: Molecules as dual inhibitors were designed successfully by the application of scaffold hopping and molecular hybridization. Designed molecules demonstrated excellent molecular docking and dynamics simulation results with an appropriate ADMET profile.

CONCLUSION: These findings strongly suggest the potential of VDK12 and VDK14 as dual inhibitors of GSK-3β and CK-1δ, offering a promising foundation for the development of new lead compounds for AD treatment.},
}

@article {pmid42083963,
year = {2026},
author = {Kanojia, N and Deswal, G and Grewal, AS and Kumar, J and Thapa, K and Sharma, A and Sharma, A and Dheer, D and Puri, V and Rani, L and Saini, V},
title = {Advances in Microneedle Technology for Targeted Therapy in Alzheimer's and Parkinson's Disease.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018425956260117232402},
pmid = {42083963},
issn = {1875-5704},
abstract = {INTRODUCTION: The fourth major cause of death worldwide is Neurodegenerative Diseases (NDs), including Alzheimer's and Parkinson's disease. The existing therapies have only a small effect on alleviating symptoms, mainly because the therapeutic agents are difficult to cross the bloodbrain barrier. The purpose of the review is to discuss the potential of microneedle-based transdermal delivery systems to improve the delivery of drugs to the central nervous system and thereby manage neurodegenerative diseases effectively.

METHODS: The article summarizes and synthesizes the available literature that targets the strategies of microneedle-mediated drug delivery. The literature on the design, composition, pharmacokinetics, and mechanistic benefits of different microneedle platforms for surmounting central nervous system barriers was identified and thematically synthesized.

RESULTS: Microneedle systems have emerged as non-invasive delivery systems with the potential for localized and sustained drug delivery, overcoming the stratum corneum and the blood-brain barrier. Micro-needles can be used to deliver small molecules, peptides, and nanoparticles to the brain, thereby avoiding systemic side effects and enhancing drug bioavailability. Some of those designs include dissolving, coated, hollow, hydrogel-forming, and stimuli-responsive microneedles, which have been shown to target the brain and exhibit higher therapeutic efficiency in preclinical models.

DISCUSSION: Although technological advances have improved, the clinical translation of microneedlebased strategies remains limited. The future directions could include using microneedles with stem cell-based therapies, CRISPR/Cas9 gene editing, artificial intelligence-based delivery systems, and responsive release technology to facilitate customized treatment.

CONCLUSION: The Microneedle-based drug delivery systems are promising in overcoming the current limitations in the treatment of neurodegenerative diseases. Nonetheless, a large-scale clinical validation is necessary to guarantee safety, efficacy, and scalability to be applied to real-life scenarios.},
}

@article {pmid42083975,
year = {2026},
author = {Saffold, K and Tall, A and Lowery, AT and Pryor, T and Jones-Muhammad, M and Shao, Q and Warrington, JP},
title = {Mouse Offspring Exposed to Preeclampsia/Eclampsia-like Symptoms Exhibit Cerebral Hypoperfusion & Mild Cognitive Impairment at 2 months of age.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00711.2025},
pmid = {42083975},
issn = {1522-1539},
support = {5R25HL145817//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1 R56 HL159447//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30GM103328//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; Startup/Bridge Funds from the Department of Neurology//University of Mississippi (UM)/ ; },
abstract = {Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20[th] week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures during pregnancy) are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared to those born from normal pregnancies. The contributing mechanisms are unknown. In this study, we assessed whether exposure to reduced uteroplacental perfusion (RUPP), modeling placental hypoperfusion and preeclampsia, with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in cognitive impairment, Alzheimer's disease markers, and regional cerebral perfusion changes in adult offspring. On gestational day (GD)13.5, pregnant C57BL/6 mice (n=22) underwent Sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD18.5. At 2 months of age, spatial learning and cerebral perfusion were measured in randomly selected offspring or averaged to obtain mean data per sex, per litter (n=4-6 data points per group/treatment). RUPP-exposed offspring took a longer distance and made more errors navigating the Barnes maze. Cerebral perfusion was reduced in offspring exposed to RUPP, specifically in the prefrontal cortex, superior sagittal sinus, and whole brain. There was a significant reduction in perfusion in seizure-exposed offspring in the superior sagittal and transverse sinuses, whole brain, and cerebellum. Our results support the hypothesis that exposure to preeclampsia/eclampsia-like symptoms leads to mild learning impairment through reduced cerebral perfusion to cortical regions and decreased drainage of waste from the brain via the cerebral sinuses.},
}

@article {pmid42083983,
year = {2026},
author = {Au, R and Gifford, KA and Paschalidis, IC and Wighton, P and Levin, M and Imam, F and Bose, N and Pratap, A},
title = {The myth of digital biomarkers in Alzheimer's disease: how to make them a reality.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42083983},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: With an estimated 41.1B digital devices, the term "digital biomarkers" has been increasingly bandied about in the research literature. There is, however, a significant disconnect between the presumption of digital biomarkers and the reality of digital biomarkers.

RECENT FINDINGS: The research literature embraces the concept of digital biomarkers without concomitant evidence for validation of digital measures as biomarkers. Unlike imaging or blood-based biomarkers, there is a woeful lack of research dedicated to validating digital measures as biomarkers. This gap also presents an opportunity. Regulatory agencies worldwide have long-standing protocols used by pharmaceutical and biotech companies to stand up quality management systems (QMS) that track research from inception to regulatory approved submissions. The recent United States (US) Food and Drug Administration (FDA) approval of Alzheimer's disease (AD) plasma biomarkers is another example where successful QMS implementation provided the processes and transparency necessary to obtain approval. Regulatory guidelines for digital technology validation are more circumspect on validation pathways of AD digital biomarkers, but FDA provides a framework for building a QMS that could potentially do so.

SUMMARY: Building an open source QMS for AD digital biomarker validation will be a critical breakthrough for harnessing the potential of digital technologies for detection, monitoring and treatment of AD and related disorders.},
}

@article {pmid42084056,
year = {2026},
author = {Komoto, Y and Takahagi, W and Ohshiro, T and Nishihata, S and Fujishima, K and Taniguchi, M},
title = {Single-molecule detection of amino acid phosphorylation using electron tunnelling currents: toward neurodegenerative disease diagnosis.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6nr00687f},
pmid = {42084056},
issn = {2040-3372},
abstract = {Protein phosphorylation is one of the most prevalent post-translational modifications regulating biological functions, and its dysregulation is closely associated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Despite extensive studies, direct detection of phosphorylation at the single-molecule level remains challenging because conventional mass spectrometry and antibody-based assays require complex pretreatments and cannot comprehensively resolve site-specific modifications. To address this challenge, we employed mechanically controllable break junction (MCBJ) measurements to probe the single-molecule conductance of serine (Ser), threonine (Thr), tyrosine (Tyr), and their phosphorylated counterparts. Distinct conductance trends were observed depending on the amino acid species, reflecting the influence of phosphate substitution on the electronic states. Density functional theory (DFT) calculations revealed that phosphorylation-induced shifts in HOMO levels and changes in π-conjugation account for the observed conductance variations. Furthermore, statistical analysis combined with machine-learning-based classification enabled discrimination between phosphorylated and non-phosphorylated amino acids with high accuracy, demonstrating that single-molecule electrical signals contain sufficient molecular information for identifying phosphorylation. This study establishes an electronic readout approach for amino acid phosphorylation and provides a proof of concept for extending single-molecule electrical techniques toward quantitative and sequencing-oriented analyses of protein modifications.},
}

@article {pmid42084083,
year = {2026},
author = {Boutajangout, A and Masurkar, AV and Osorio, R and Debure, L and Ghuman, M and Ahmed, W and Vedvyas, A and Pirraglia, E and Links, J and Bokacheva, L and Vega, B and Bernard, MA and Marsh, K and Bubu, OM and Shao, Y and Chodosh, J and Rusinek, H and Wisniewski, T},
title = {Association of plasma biomarkers with amyloid and tau PET in pre-dementia stages.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71441},
doi = {10.1002/alz.71441},
pmid = {42084083},
issn = {1552-5279},
support = {P30AG066512//National Institutes of Health grants/ ; R01AG077422//National Institutes of Health grants/ ; U24NS141774//National Institutes of Health grants/ ; U24NS141774/NS/NINDS NIH HHS/United States ; R01AG077422/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood/metabolism ; *Biomarkers/blood ; Male ; *Positron-Emission Tomography ; Female ; *Amyloid beta-Peptides/blood ; *Cognitive Dysfunction/blood/diagnostic imaging ; Aged ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Middle Aged ; Peptide Fragments/blood ; Alzheimer Disease/blood/diagnostic imaging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease.

METHODS: Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively.

RESULTS: Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001).

DISCUSSION: Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.},
}

Humans
*tau Proteins/blood/metabolism
*Biomarkers/blood
Male
*Positron-Emission Tomography
Female
*Amyloid beta-Peptides/blood
*Cognitive Dysfunction/blood/diagnostic imaging
Aged
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Middle Aged
Peptide Fragments/blood
Alzheimer Disease/blood/diagnostic imaging
Aged, 80 and over

@article {pmid42084109,
year = {2026},
author = {Gabel, M and Goswami, S and Bekena, S and Solomon, ED and Moulder, KL and Morris, JC and Mozersky, J},
title = {The impact of learning about financial compensation on enrollment in Alzheimer's disease longitudinal research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71356},
doi = {10.1002/alz.71356},
pmid = {42084109},
issn = {1552-5279},
support = {P01AG003991/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; P01AG026276/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/economics/psychology ; Female ; Longitudinal Studies ; Male ; *Patient Selection ; Aged ; Aged, 80 and over ; *Compensation and Redress ; },
abstract = {INTRODUCTION: Recruitment and retention remains a major challenge in Alzheimer's disease research. This study examined the impact of describing potential financial compensation during recruitment on participant enrollment to a longitudinal cohort.

METHODS: Participant recruitment calls (N = 337) were randomized to either a compensation-mentioned group (n = 170) or a control group (n = 167). An intention-to-treat logistic regression assessed the effect of compensation on enrollment.

RESULTS: Of 320 analyzed, 124 (38.75%) enrolled. The intervention group's consent rate was lower than the control group's in intention-to-treat (-9.72 points; p = 0.074), per-protocol (-12.72 points; p = 0.026), and complier average causal effect analyses (-11.36 points; p = 0.72).

DISCUSSION: Disclosing compensation during recruitment may reduce enrollment, potentially due to perceptions that compensation conflicts with altruistic motives. However, this was observed in a highly educated sample; compensation may affect those with lower levels of education and socioeconomic status differently by helping offset participation burden, warranting further investigation.},
}

Humans
*Alzheimer Disease/economics/psychology
Female
Longitudinal Studies
Male
*Patient Selection
Aged
Aged, 80 and over
*Compensation and Redress

@article {pmid42084231,
year = {2026},
author = {Barolo, L and Farina, MV and Cimaglia, G and Gigante, Y and Mirone, A and Mautone, L and Boffi, A and Di Angelantonio, S and Baiocco, P},
title = {From Food Additives to Neurodegeneration: The Emerging Role of Polyphosphates in Tauopathies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00915},
pmid = {42084231},
issn = {1948-7193},
abstract = {Neurodegenerative diseases are characterized by progressive molecular and biochemical dysfunctions that disrupt neuronal homeostasis, leading to impaired nervous system function. In tauopathies, a specific class of neurodegenerative disorders, tau protein aggregation and mitochondrial dysfunction are pathological processes interconnected in a self-reinforcing cycle. In fact, tau fibrils impair mitochondrial transport, bioenergetics, and quality control, while mitochondrial dysregulation causes tau post-translational modifications, detachment from neurons, and aggregation. In this context, inorganic polyphosphates located in cells are recently emerging as a possible modulator of both tau aggregation and mitochondrial dysfunction, thereby contributing to the onset and progression of tauopathies, including Alzheimer's disease. Additionally, inorganic polyphosphates are widely present in diets worldwide as food additives, suggesting a possible frightening connection between nutrition and tauopathies, especially in vulnerable individuals. Understanding these biochemical and nutritional interactions may support the development of novel therapeutic approaches and provide effective preventive strategies to mitigate the risk of neurodegeneration in aging populations. This review explores the current state of the art for in vivo and in vitro studies, exploring the role of endogenous polyphosphates in tau aggregation and mitochondrial dysfunction, including a novel focus point: how exogenous polyphosphates present in everyday processed food could potentially facilitate the onset of pathological conditions in humans.},
}

@article {pmid42084241,
year = {2026},
author = {Bae, Y and Kim, M and Jeon, SR and Lee, SW and Jung, H},
title = {Risk of Alzheimer Disease and Other Dementias in Patients With Parkinson Disease: A Nationwide Cohort Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000722},
pmid = {42084241},
issn = {1546-4156},
abstract = {INTRODUCTION: Dementia is a major nonmotor complication of Parkinson disease (PD), yet its subtype-specific and time-dependent risk remains incompletely characterized.

METHODS: We conducted a nationwide retrospective cohort study using Korean National Health Insurance claims and health screening data. Newly diagnosed PD patients (ICD-10: G20) and propensity score-matched controls were followed after a 3-year washout period. Dementia outcomes were defined using ICD-10 codes and classified as Alzheimer disease dementia (F00, G30), other dementias (F01-F03), and overall dementia. Incidence rate ratios (IRRs) and adjusted hazard ratios (aHRs) were estimated using Cox models.

RESULTS: PD was associated with higher dementia incidence across all subtypes. IRRs were 3.38 (95% CI: 3.12-3.67) for Alzheimer disease dementia, 4.67 (95% CI: 4.16-5.23) for other dementias, and 3.60 (95% CI: 3.33-3.90) for overall dementia. Elevated risks persisted after multivariable adjustment and were more pronounced in younger patients and men, with variation by dementia subtype and time since diagnosis.

CONCLUSIONS: PD was associated with an increased risk of dementia in this nationwide cohort. The heterogeneity observed by subtype, age, and follow-up period suggests that dementia risk may emerge early in specific subgroups, supporting early cognitive monitoring without implying causality.},
}

@article {pmid42084363,
year = {2026},
author = {Wu, L and Li, S and Huang, L and Li, L and Zhou, P and Lu, Z and Liu, T and Wang, J},
title = {Non-Invasive Temporal Interference Electrical Stimulation Modulates Neurotransmitter Release and Improves Aberrant Neural Oscillations in Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70848},
doi = {10.1002/cns.70848},
pmid = {42084363},
issn = {1755-5949},
support = {2025SF-YBXM-254//Shaanxi Province Key Research and Development Program Project/ ; 82102179//National Natural Science Foundation of China/ ; ZR2024QF287//Natural Science Foundation of Shandong Province/ ; ZR2024YQ077//Natural Science Foundation of Shandong Province/ ; tsqn202211226//Taishan Scholar Foundation of Shandong Province/ ; tstp20221144//Taishan Scholar Foundation of Shandong Province/ ; K2025LC0102//Clinical Research Capacity Improvement Special Project of University of Health and Rehabilitation Sciences/ ; SRICSPYF-BS2025076//Scientific Research Innovation Capability Support Project for Young Faculty/ ; },
mesh = {Animals ; *Alzheimer Disease/therapy/physiopathology/metabolism/genetics ; Mice, Transgenic ; Mice ; *Neurotransmitter Agents/metabolism ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Male ; Humans ; *Electric Stimulation Therapy/methods ; Presenilin-1/genetics ; Mice, Inbred C57BL ; *Brain/physiopathology/metabolism ; },
abstract = {BACKGROUND: Modulating brain oscillations has significant therapeutic promise. Traditional non-invasive neuromodulation techniques can alleviate clinical signs of Alzheimer's disease (AD) by restoring normal neural oscillatory activity in certain brain regions. As a novel non-invasive brain modulation technique, temporal interference (TI) has been demonstrated to precisely control hippocampus neural oscillations while minimizing its impact on cortical neural activity, but its exact mechanism of action is still unclear.

METHOD: We simulated and experimentally measured the intracranial electric field under TI to determine the precision of TI intervention. Subsequently, TI stimulation was applied to the APP/PS1 transgenic AD mouse model, and the impact of TI stimulation on the stimulated brain region was compared from the perspectives of behavior, electrophysiology, and cell biology.

RESULTS: This work showed that in the APP/PS1 Alzheimer's disease mice model, TI stimulation significantly increased GABA levels and decreased NMDA receptor activation at the targeted region. Following neurotransmitter regulation, the rhythm of the gamma oscillations they associate also changed. This, in turn, influenced other memory-related neural oscillation frequencies and brain regions through cross-frequency coupling and brain connectivity, ultimately improving the behavioral performance of AD model mice.

CONCLUSIONS: The results of our work demonstrated how TI stimulation alters brain oscillations to enhance memory in mice with Alzheimer's disease, offering a possible theoretical foundation for TI's clinical application.},
}

Animals
*Alzheimer Disease/therapy/physiopathology/metabolism/genetics
Mice, Transgenic
Mice
*Neurotransmitter Agents/metabolism
Disease Models, Animal
Amyloid beta-Protein Precursor/genetics
Male
Humans
*Electric Stimulation Therapy/methods
Presenilin-1/genetics
Mice, Inbred C57BL
*Brain/physiopathology/metabolism

@article {pmid42084488,
year = {2026},
author = {Hernandez, A and Massihzadegan, S and Coyle, C},
title = {Adult Social Day Services: A Promising, Yet Underutilized Community-Based Support for Individuals With Alzheimer's Disease and Related Dementias.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261448267},
doi = {10.1177/07334648261448267},
pmid = {42084488},
issn = {1552-4523},
abstract = {As Alzheimer's disease and related dementias (ADRD) become more common, there is a growing need for programs that improve the quality of life for individuals living with these conditions. Understanding existing community-based models of engagement is essential for identifying effective, scalable solutions. Adult Social Day Services (ASDS) offer opportunities for socialization and cognitive engagement for individuals who require minimal assistance with activities of daily living. Although promising, ASDS programs are used unevenly, and their overall effectiveness remains unclear. To address this gap, we conducted a parallel convergent mixed-methods study using data from a fee-based ASDS program located at a senior center in a northeastern U.S. town. Using a population-level survey, stakeholder focus groups, and in-depth interviews with current and former participants and their families, we examined the program from multiple perspectives. Findings suggest the ASDS model has strong potential for scaling, replication, and adaptation as a community-based dementia intervention, with benefits for participant well-being and caregiver support.},
}

@article {pmid42084584,
year = {2026},
author = {Lee, S and Gunaga, S and Liu, SW and Luo, Q and Bayer, TA and Rudolph, JL and Carnahan, RM},
title = {Emergency Department Boarding for Older Adults: The Impact of Geography, Temporal Trends, and Dementia Status.},
journal = {Annals of emergency medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.annemergmed.2026.03.011},
pmid = {42084584},
issn = {1097-6760},
abstract = {STUDY OBJECTIVE: Emergency department (ED) boarding, defined as the time an admitted patient remains in the ED awaiting an inpatient bed, has become a growing challenge in the United States, particularly for older adults with Alzheimer's disease-related dementia. We examined trends in ED boarding from 2015 to 2022, focusing on geographic variation, rurality, and differences by Alzheimer's disease-related dementia status.

METHODS: We conducted a cross-sectional analysis using National Hospital Ambulatory Medical Care Survey (NHAMCS) data from 2015 to 2022. Adults aged ≥65 years who were admitted to the hospital were included. Weighted estimates characterized annual boarding rates (≥2, 4, and 8 hours). Linear probability models assessed associations of study year, region, rurality, and Alzheimer's disease-related dementia status with boarding as binary outcomes; linear regression examined boarding duration in minutes.

RESULTS: Among an estimated 7.05 million eligible encounters, 4.45 million had complete data; 85.2% experienced boarding ≥2 hours. Rates remained in the mid-80% range from 2015 to 2018, dipped in 2017 and 2020, and rose to 92% in 2021 to 2022. Mean boarding time increased from 138 minutes (95% confidence interval [CI] 112 to 164) in 2018 to 343 minutes (95% CI 238 to 448) in 2022, reaching 501 minutes (95% CI -20 to 1,022) among patients with Alzheimer's disease-related dementia. Each additional calendar year was associated with a 3.2% increase in 4-hour boarding (95% CI 2.4% to 4.0%) and 15.3 more minutes of boarding time (95% CI 10.0 to 20.0). In the Alzheimer's disease-related dementia subgroup, boarding increased most among those aged ≥75 years and in metropolitan areas.

CONCLUSION: Emergency department boarding among older adults has worsened over time, especially for those with Alzheimer's disease-related dementia. Regional disparities and disproportionate impacts on vulnerable populations highlight the urgent need for targeted policy and operational interventions.},
}

@article {pmid42084750,
year = {2026},
author = {Hafez, MM and Abbas, HA and Shoman, NA and Soubh, AA and Aly, O and Sallam, MF and Seliem, M and Malaak, FA},
title = {A new era in neuropharmacology: assessing the efficacy and safety of novel anti-amyloid and non-amyloid drug targets for Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42084750},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuropharmacology/trends/methods ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Animals ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia in the world with the prevalence expected to increase threefold to 152.8 million people by 2050. The current medications provide a short-term ameliorative effect, and this requires development of disease-modifying treatments, which address the biological pathogenesis.

METHODS: This review assesses the changing neuropharmacological environment offering a critical analysis of anti-amyloid monoclonal antibodies and investigates the so-called expanding frontier of non-amyloid targets. It also examines the approaches of clinical trials and the trend of biomarker-based patient selection and precision medicine.

RESULTS: Although β-site APP-cleaving enzyme 1 (BACE1) and secretase inhibitors did not achieve success in clinical trials because of mechanism-based toxicity and cognitive impairment, new monoclonal antibodies such as lecanemab and donanemab have shown high amyloid plaque clearance and reduced cognitive deterioration. Nevertheless, the treatments are associated with amyloid-related imaging abnormalities (ARIA). In addition to amyloid, studies are focusing on tau hyperphosphorylation, neuroinflammation through triggering receptor on myeloid cells 2 (TREM2) and NLR family pyrin domain containing 3 (NLRP3) and growth factor-mediated synaptic plasticity through brain-derived neurotrophic factor (BDNF).

CONCLUSIONS: AD treatment has entered the new era that demands a paradigm shift from monotherapies to multi-target cocktails. The future lies in precision neuropharmacology, where genetic stratification and individual biomarker analysis are used to provide the correct treatment at the most appropriate biological stage.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuropharmacology/trends/methods
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Antibodies, Monoclonal/therapeutic use/pharmacology
Animals

@article {pmid42084972,
year = {2026},
author = {Kumar, D and Singh, SB and Sagar, V and Prasad, MK and Kapoor, N and Mukul, A and Nishant, A},
title = {Breakthrough Vaccines and Transformative Therapies on the Horizon of Progress toward Diabetes Management.},
journal = {Indian journal of public health},
volume = {},
number = {},
pages = {},
doi = {10.4103/ijph.ijph_102_25},
pmid = {42084972},
issn = {0019-557X},
abstract = {Diabetes mellitus (DM) affects millions of people globally. Over the years, diabetes has emerged as a significant global health concern, with steadily increasing prevalence. This review explores the various aspects of DM and delves into the evolving field of new emerging treatments and diabetes vaccines, highlighting the potential they hold in revolutionizing diabetes management in the future. Therefore, it is imperative to know about the potential vaccines and novel emerging treatment options for DM and to understand the challenges faced in making novel therapies. It is also needed to recognise the intricate relationship between diabetes and Alzheimer's disease, an emerging entity known as type 3 diabetes. Literature search was done in PubMed database, and relevant articles were selected for the narrative review. The review reveals that currently, most vaccines that have been developed are in animal studies and early phases of trials. Only few human trials have been conducted, but, with positive outcome. There are also some novel therapeutics emerging as potential management options for diabetes. There are evidences to support that Alzheimer's disease can rightly be called type 3 diabetes. In conclusion, there is a growing interest in the development of vaccines as a revolutionary approach to diabetes management. As our understanding of diabetes deepens and vaccine technology advances, the prospect of a diabetes vaccine becoming a reality offers hope for millions living with this condition and in reducing the burden of diabetes-related complications.},
}

@article {pmid42085565,
year = {2026},
author = {Singh, K and Ahmad, I and Jain, D and Mim, TJ and Noman, AA and Shihab, MPR and Kondaveeti, SB and Gupta, JK and Wal, P},
title = {Novel Cellular Signalling Axes in Neurodegenerative Diseases: From NLRP3 Inflammasome to Wnt/β-Catenin and Hippo-YAP Pathways.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70880},
doi = {10.1002/jbt.70880},
pmid = {42085565},
issn = {1099-0461},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Wnt Signaling Pathway ; Animals ; Hippo Signaling Pathway ; *beta Catenin/metabolism ; YAP-Signaling Proteins ; *Adaptor Proteins, Signal Transducing/metabolism ; *Protein Serine-Threonine Kinases/metabolism ; *Transcription Factors/metabolism ; Signal Transduction ; },
abstract = {Neurodegenerative diseases (NDs), including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), are characterised by impaired cellular homeostasis and progressive neuronal loss. Emerging evidence highlights the critical role of cellular signalling pathways in the progression and pathogenesis of these disorders. With a focus on the NLRP3 inflammasome, Wnt/β-catenin, and Hippo-YAP cascades, this review focuses on new signalling pathways linked to neurodegenerative disorders. Among them, the NLRP3 inflammasome is a crucial mediator of neuroinflammation, causing neuronal damage and persistent immune activation. In contrast, these pathways regulate neurogenesis, synaptic plasticity, and cell survival, offering potential neuroprotective functions. Dysregulation of these pathways disrupts cellular integrity, exacerbates disease progression, and represents a convergence point for therapeutic intervention. In NDs, knowing how these pathways interact offers fresh perspectives on disease processes and finds new targets for the creation of disease-modifying treatments.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Inflammasomes/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Wnt Signaling Pathway
Animals
Hippo Signaling Pathway
*beta Catenin/metabolism
YAP-Signaling Proteins
*Adaptor Proteins, Signal Transducing/metabolism
*Protein Serine-Threonine Kinases/metabolism
*Transcription Factors/metabolism
Signal Transduction

@article {pmid42085591,
year = {2026},
author = {Martínez-Bujidos, M and Menéndez, A and Pulido-Gracia, JA and Vilas, D and Samaniego, D and Ispierto, L and Morales-Indiano, C and Pastor, P},
title = {Analytical agreement and platform-specific decision thresholds for plasma p-tau217 measured on Lumipulse G600II and Cobas e801 in a paired CSF-plasma cohort.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42085591},
issn = {1437-4331},
abstract = {OBJECTIVES: Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a highly accurate blood-based biomarker of Alzheimer's disease (AD) pathology. As disease-modifying anti-amyloid therapies enter clinical practice, scalable biomarkers with robust and clinically interpretable decision thresholds are required. However, evidence on inter-platform comparability and threshold transferability across automated assays remains limited.

METHODS: We conducted a head-to-head comparison of two automated platforms - Lumipulse[®] G600II and Cobas[®] e801 - for plasma p-tau217 measurement in 157 consecutive patients undergoing lumbar puncture. Amyloid status was defined by the CSF Aβ42/Aβ40 ratio. Agreement was assessed using intraclass correlation coefficients and Bland-Altman analysis. Diagnostic performance was evaluated using receiver operating characteristic curves. Optimal thresholds were derived using the Youden index. Predefined rule-out (≥95 % sensitivity) and rule-in (≥95 % specificity) thresholds were explored, alongside alternative ≥90 % thresholds.

RESULTS: Agreement between platforms was excellent (Spearman ρ=0.922; ICC(3,1)=0.922), although Bland-Altman analysis revealed a small systematic difference in absolute concentrations. Both assays showed comparable diagnostic accuracy for amyloid positivity (AUC=0.923 for both platforms; DeLong p>0.99), but required platform-specific thresholds. Rule-out and rule-in thresholds achieved ≥95 % sensitivity and specificity, with strong likelihood ratios and excellent categorical agreement (weighted κ=0.870). Approximately 30 % of individuals were classified in the grey zone. Using ≥90 % thresholds reduced the grey zone to 9-13 % while maintaining excellent agreement.

CONCLUSIONS: Plasma p-tau217 demonstrates high analytical concordance and comparable diagnostic performance across automated platforms despite systematic concentration differences. Platform-specific dual-threshold strategies may support structured and clinically interpretable implementation, pending prospective multicenter validation.},
}

@article {pmid42085745,
year = {2026},
author = {Xie, R and Lin, X and Chen, S and Li, J and Zhou, J and Xu, K and Zheng, Y and Huang, W and Zhang, L},
title = {Aortic aneurysm and dissection and its multidimensional impact on cognitive function: The pivotal role of PRDX6 in pathophysiological mechanisms.},
journal = {Atherosclerosis},
volume = {417},
number = {},
pages = {120773},
doi = {10.1016/j.atherosclerosis.2026.120773},
pmid = {42085745},
issn = {1879-1484},
abstract = {AIMS: This study aims to explore the relationship between aortic aneurysm and dissection (AAD) and cognitive impairment, with an emphasis on uncovering the potential biological mechanisms.

METHODS: Utilizing the UK Biobank database, a matched cohort study was performed to assess the association between AAD and the risk of Alzheimer's disease. Cognitive function was evaluated in a β-aminopropionitrile (BAPN)-induced AAD mouse model through a series of behavioral assays. Drug-target Mendelian randomization analysis was conducted to identify candidate genes implicated in this association. Expression levels of PRDX6 were examined in brain tissues from Alzheimer's disease patients using datasets from the Gene Expression Omnibus (GEO), as well as in aortic tissues and blood samples obtained from both AAD patients and AAD model mice. Correlative analyses between PRDX6 and pro-inflammatory cytokines (IL-1β and TNF-α) were performed in mouse hippocampal tissues of the mouse model. Additionally, in vitro experiments employing SH-SY5Y cells were carried out to investigate the functional role of PRDX6 in modulating synaptic protein expression and inflammatory responses.

RESULTS: Competing risk regression analysis indicated that AAD is significantly associated with an increased incidence of cognitive impairment. Behavioral testing revealed that AAD model mice exhibited deficits in cognitive performance. Mendelian randomization prioritized PRDX6 was prioritized as a candidate gene of interest. Elevated PRDX6 expression was observed in brain tissues from Alzheimer's disease patients. Both AAD patients and AAD model mice demonstrated markedly increased PRDX6 levels in aortic tissues and circulating blood; notably, PRDX6 expression was also upregulated in the hippocampus of AAD mice. In the hippocampus, PRDX6 expression positively correlated with levels of IL-1β and TNF-α expression in AAD mice. In SH-SY5Y cells, silencing of PRDX6 resulted in increased expression of synaptic proteins, reduced pro-inflammatory cytokine production, and decreased apoptosis, whereas overexpression of PRDX6 elicited inverse effects.

CONCLUSIONS: The present findings establish a significant association between AAD and heightened risk of cognitive impairment. PRDX6 has been identified as a potential mediator in this relationship, and PRDX6-related neuroinflammation is proposed as a plausible mechanistic pathway linking AAD to cognitive dysfunction.},
}

@article {pmid42085824,
year = {2026},
author = {Gaba, A and Li, P and Cai, R and Chhajed, M and Hu, K and Gao, L},
title = {Fractal cardiac activity regulation during exercise and delirium risk in older adults.},
journal = {Archives of gerontology and geriatrics},
volume = {148},
number = {},
pages = {106264},
doi = {10.1016/j.archger.2026.106264},
pmid = {42085824},
issn = {1872-6976},
abstract = {OBJECTIVES: Delirium, acute confusion marked by fluctuations of attention and concentration, is associated with increased risk for poor long-term health outcomes, including Alzheimer's disease (AD), institutionalization, and mortality. Cardio-autonomic control is implicated in modulating response to acute stressors, and alteration is separately shown to predict mortality. Heart rate (HR) fluctuations display fractal correlations (similar temporal autocorrelation across different time scales) that reflect a dynamic interplay between sympathetic and vagal outflows, where disruption is thought to contribute to neuronal damage. We hypothesized that fractal cardiac activity regulation FCAR (α1) correlations in HR predicts incident delirium.

DESIGN: Prospective cohort study using UK Biobank data.

SETTING: Community-based participants undergoing ECG-monitored exercise testing.

PARTICIPANTS: 41,109 adults (mean age 58.0 years) free from delirium or AD at baseline who completed a 7-minute stationary bike test (2009-2010) and had ≥1 hospitalization by March 2021.

MEASUREMENTS: Detrended fluctuation analysis was used to derive short-term fractal scaling exponents (α1) from ECG data. Cox proportional hazard models examined the association between FCAR (α1) and incident delirium, adjusting for demographics, lifestyle, comorbidities cognition, and exercise parameters.

RESULTS: Over a median of 11.4 years (IQR 11.3-11.5), 442 cases (11 per 1000) developed delirium. FCAR (α1) was normally distributed, (mean 1.25 ± 0.35 (SD)). Compared to those in the highest FCAR (α1) quartile (>1.50), participants in the lowest quartile (<1.01) had a 40% increased risk of delirium (HR 1.40; 95% CI: 1.05-1.88; p = 0.02). This risk increase was equivalent to being 3.3 years older in the fully adjusted models.

CONCLUSIONS: Lower FCAR (α₁) during exercise predicted higher long-term risk of delirium, suggesting a potential prognostic indicator associated with brain-heart resilience. Future research should examine its role in shared vulnerability to delirium and neurodegenerative disorders.},
}

@article {pmid42085850,
year = {2026},
author = {Xu, Y and Liang, W and Tang, Z and Lu, F and Xia, L and Xie, H and Zhong, M and Li, S},
title = {Akt at the crossroads of microglial function: a double-edged sword in Alzheimer's disease neuroinflammation.},
journal = {International immunopharmacology},
volume = {181},
number = {},
pages = {116773},
doi = {10.1016/j.intimp.2026.116773},
pmid = {42085850},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) pathology is increasingly understood to be driven by complex neuroinflammatory processes, with microglia-the resident immune cells of the brain playing a pivotal role. The PI3K/Akt signaling pathway serves as a critical intracellular hub, orchestrating the diverse and often opposing functions of microglia. This review synthesizes current insights into the multifaceted role of Akt signaling in modulating microglial activity in the context of AD. We explore the dualistic nature of Akt, which can promote pro-inflammatory neurotoxicity through pathways such as NF-κB while simultaneously mediating neuroprotective functions, including anti-inflammatory resolution, amyloid-β (Aβ) phagocytosis, and regulation of key clearance receptors like triggering receptor expressed on myeloid cells 2 (TREM2). Additionally, we examine how the Akt/mTOR axis governs microglial immunometabolism, facilitating the transition between glycolytic, pro-inflammatory states and oxidative phosphorylation-driven, phagocytic phenotypes. Emerging therapeutic strategies are discussed, including natural compounds, pharmacological agents, indirect modulation via the gut-brain axis and physical brain stimulation, as well as advanced nanotechnology platforms designed to target this pathway in microglia with precision. Finally, we address key challenges such as isoform specificity, therapeutic timing, and translational relevance, and outline future perspectives aimed at achieving "precision immunomodulation" of the Akt pathway. Such fine-tuning of microglial function represents a promising yet complex avenue for developing effective therapies to combat AD.},
}

@article {pmid42070356,
year = {2026},
author = {Arancibia-Díaz, A and Trujillo-Fernández, S and Astudillo-Castro, C and Vergara-Castro, M and Soto-Maldonado, C and Córdova, A and Zúñiga-Hansen, ME and Vega-Letter, AM and Fuentes, P and Altamirano, C},
title = {Neuroprotective and antioxidant effects of fermented spent coffee ground fractions against Alzheimer's-related oxysterol 27-hydroxycholesterol in SH-SY5Y neuronal cells.},
journal = {Food chemistry},
volume = {517},
number = {},
pages = {149435},
doi = {10.1016/j.foodchem.2026.149435},
pmid = {42070356},
issn = {1873-7072},
abstract = {Spent coffee grounds (SCG) constitute a phenolic-rich agro-industrial residue with underexplored biomedical potential. This study developed a sequential bioprocess comprising solid-state fermentation, hydroalcoholic extraction, and ultrafiltration to selectively enrich low-molecular-weight phenolic fractions and assess their effects in Alzheimer's-related stress conditions. Phenolic compounds Total (TPC) and composition were quantified, and bioactivity was assessed in SH-SY5Y neuronal cells exposed to hydrogen peroxide (H2O2) or the oxysterol 27-hydroxycholesterol (27-OHC), a key driver of redox imbalance and amyloidogenic pathways. Assessed parameters included cell density and viability, reactive oxygen species (ROS), superoxide dismutase (SOD) activity and amyloid-β peptide 40 (Aβ40) accumulation. Bioprocessing enhanced the total phenolic content by up to 4.2-fold and redirected the metabolite profiles toward highly diffusible, low-molecular-weight compounds. The <3 kDa fraction exhibited the strongest functional response, markedly suppressing ROS generation (∼90%), restoring SOD activity and reducing Aβ40 levels under 27-OHC challenge. These results evidence an enrichment strategy that yields SCG-derived fractions with potent antioxidant and neuroprotective properties.},
}

@article {pmid42070480,
year = {2026},
author = {Lu, SY and Zhu, Z and Zhang, B and Zhang, YD and Yao, YD},
title = {A lightweight vision transformer with context-aware convolution and uniformity normalization for Alzheimer's Disease diagnosis.},
journal = {Computer methods and programs in biomedicine},
volume = {282},
number = {},
pages = {109413},
doi = {10.1016/j.cmpb.2026.109413},
pmid = {42070480},
issn = {1872-7565},
abstract = {BACKGROUND: Early and accurate diagnosis of Alzheimer's Disease (AD) is crucial for effective clinical intervention.

METHOD: In this study, we propose a lightweight vision transformer architecture specifically designed for AD classification using 2D brain MRI slices. LICAUN-ViT incorporates three key innovations: Mono-Head Self-Attention (MOHSA) to reduce computational overhead, Uniformity Normalization (Uni-Norm) to mitigate oversmoothing and enhance feature diversity, and Context-Aware Convolution (CAC) to integrate long-range dependencies with local structural features.

RESULTS: Evaluated on two benchmark datasets derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI), our model achieves state-of-the-art performance with an accuracy of 93.03 % on axial slices and 94.15 % on sagittal slices, while maintaining relatively low floating-point operations (FLOPs) for efficient deployment. Extensive ablation studies and singular value analyses confirm the effectiveness and robustness of the proposed components.

CONCLUSION: These results demonstrate that the proposed model offers a computationally efficient and promising solution for automated AD diagnosis, with strong potential for clinical integration.},
}

@article {pmid42070656,
year = {2026},
author = {Molinatti, F and De Gracia, L and Oliva, A},
title = {Descriptive analysis of mortality due to Parkinson's disease and Alzheimer disease in Argentina.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502084},
doi = {10.1016/j.nrleng.2026.502084},
pmid = {42070656},
issn = {2173-5808},
abstract = {INTRODUCTION: Parkinson's disease (PD) and Alzheimer disease (AD), along with other nervous system disorders, are the leading causes of global disease burden. Although global trends have remained stable in recent decades, an increase in years of life lost due to these diseases has been recorded. In Argentina, though no prevalence records are available for PD and AD, reliable mortality data do exist. Similarities and differences in mortality caused by PD and AD are analysed in the present study.

METHODS: The study was performed in the total population between 2000 and 2019. Age-standardised mortality rates (ASMR) were calculated. At the national level, annual trends were analysed and comparisons between provinces were made. Subsequently, spatial autocorrelation in the Centre Region (CR) was examined.

RESULTS: Between 2000 and 2019, there were no statistically significant changes in ASMR for PD or AD, in either sex. In most cases, ASMR in the CR and its provinces were higher than the national average. At the department level, a trend towards the concentration of similar values was observed, with the exception of mortality due to PD among women.

CONCLUSIONS: The CR exhibits a higher ASMR than the national average, with rates of mortality due to AD in men in Santa Fe province being particularly noteworthy. It also shows a distinct spatial concentration pattern, with 2 distinct clusters. Further research is required to investigate the underlying sociodemographic and environmental factors contributing to this pattern.},
}

@article {pmid42070757,
year = {2026},
author = {Liu, JY and Liu, SY and Ran, LX and Qiao, WH and Zhang, F and Zhang, KS and Liang, XX and Liu, MY and Yu, ZH and Wei, MJ and Zhong, X},
title = {Organelle-orchestrated cGAS-STING signaling and its role in neurodegeneration.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108216},
doi = {10.1016/j.phrs.2026.108216},
pmid = {42070757},
issn = {1096-1186},
abstract = {The cGAS-STING signaling pathway serves as a central signalling axis of the innate immune system, and its aberrant activation plays a pivotal role in inflammatory responses. Recent studies have demonstrated that its regulation depends not only on individual organelles but also on a coordinated interorganelle network. This review systematically analyze how mitochondria, centrosomes, the endoplasmic reticulum (ER), membrane contact sites (MCSs), the Golgi apparatus, endosomes, and lysosomes collectively orchestrate cGAS-STING signaling. Mitochondria initiate signaling by releasing mitochondrial DNA; centrosomes serve as platforms for double-stranded DNA accumulation to potentiate cGAS activation; the ER anchors STING in a calcium homeostasis-dependent manner; mitochondrial-associated ER membranes (MAMs) integrate calcium and lipid signaling as regulatory checkpoints governing STING trafficking to the Golgi apparatus; the Golgi amplifies downstream signaling through site-specific post-translational modifications of STING; finally, the endosome-lysosome system, together with ER-lysosome MCSs, acts as a coordinated hub for STING sorting, lysosomal degradation and signal termination. Consequently, disruption of organelle homeostasis leads to persistent STING activation. In neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease, organelle dysfunction resulting from calcium overload, impaired organelle clearance, proteolytic cleavage of tethering proteins or multi-source attacks drives aberrant STING signaling. Sustained STING activity exacerbates pathological cascades such as protein misfolding, chronic neuroinflammation, and progressive neuronal loss. Therefore, therapeutic strategies targeting key regulatory nodes of the STING pathway, from upstream organelle repair to direct pharmacological inhibition, offer significant potential to mitigate disease-associated pathological progression and constitute a promising foundation for precision therapeutics in neurodegenerative disorders.},
}

@article {pmid42071065,
year = {2026},
author = {Fikry, H and Sadek, DR and Saleh, LA and Hasanin, MTM and Alkhalek, HAA},
title = {Dual protective role of curcumin- encapsulated chitosan nanoparticles against gastric and neural injury in a rat model of gut-brain axis dysfunction: a histological and biochemical study.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42071065},
issn = {1432-1912},
abstract = {Gastric ulcer (GU) and Alzheimer's disease (AD) are prevalent age-associated disorders frequently accompanied by systemic oxidative stress and inflammation. Emerging evidence suggests that gastrointestinal dysfunction and inflammatory signaling may aggravate neurodegenerative processes. Curcumin (Cur) exhibits well-established antioxidant, anti-inflammatory, neuroprotective, and gastroprotective properties; however, its therapeutic utility is limited by poor bioavailability. The present study aimed to formulate and characterize Curcumin- encapsulated chitosan nanoparticles (Cur-CSNPs) and evaluate their dual protective effects in a clinically relevant comorbid rat model combining scopolamine-induced AD-like pathology and ethanol-induced GU. Male Wistar rats were divided into six groups: control, Cur-CS-NPs alone, GU, AD, GU + AD, and GU + AD treated with Cur-CSNPs. Behavioral assessments, biochemical analyses, histopathological evaluation, and immunohistochemical investigations were performed on brain and gastric tissues. GU + AD rats exhibited cognitive deficits, neuronal degeneration, amyloid-β accumulation, astrocyte activation, gastric mucosal injury, increased oxidative stress, NF-κB activation, elevated inflammatory cytokines, and enhanced apoptotic signaling. Cur-CSNP treatment significantly improved cognitive performance, reduced oxidative stress and inflammation, suppressed NF-κB signaling, decreased amyloid-β deposition, inhibited apoptosis, and restored gastric mucosal integrity. In conclusion, Cur-CSNPs exert concurrent neuroprotective and gastroprotective effects in a comorbid AD and GU model through coordinated modulation of oxidative stress, inflammation, amyloidogenic activity, and apoptotic pathways. These findings demonstrate that Cur-CSNPs exert dual neuroprotective and gastroprotective effects by modulating oxidative stress, inflammation, amyloidogenic pathways, and apoptosis, highlighting nano-curcumin as a promising therapeutic strategy for gut-brain axis-related disorders. Further investigations are warranted to elucidate the detailed molecular mechanisms and to explore the clinical applicability of nano-formulated curcumin as a therapeutic strategy for disorders involving concurrent gastrointestinal and neurodegenerative pathology.},
}

@article {pmid42071101,
year = {2026},
author = {Li, K and Shacham, E and Zhu, Y and Trani, JF and Babulal, GM},
title = {Driving the neural exposome: Latent mobility states from naturalistic GPS data in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71425},
doi = {10.1002/alz.71425},
pmid = {42071101},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; R01AG068183 (GMB)/AG/NIA NIH HHS/United States ; R01AG067428 (GMB)/AG/NIA NIH HHS/United States ; R01AG074302 (GMB)/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Automobile Driving ; Aged ; *Geographic Information Systems ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Aged, 80 and over ; Markov Chains ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Naturalistic driving provides real-world behavioral indicators of early cognitive and functional changes. This study integrated naturalistic driving GPS trajectories collected from in-vehicle sensors with points of interest (POIs) to quantify daily environmental engagement among older adults who were cognitively normal at enrollment.

METHODS: Data from 438 participants enrolled in the Driving Real-world in-Vehicle Evaluation System Project were used to generate daily POI share vectors and model latent engagement patterns using a logistic-normal hidden Markov model (HMM). Thirteen latent states described distinct modes of environmental interaction. From each participant's inferred state sequence, we derived mobility features - state occupancy, dwell time, transition entropy, and self-transition probability - and examined their differences across clinical status groups and associations with Preclinical Alzheimer's Cognitive Composite (PACC) performance.

RESULTS: Transition entropy and several state-specific occupancy and dwelling metrics differed across clinical groups, but none of the mobility features were significantly associated with PACC scores.

DISCUSSION: Mobility-derived behavioral features differentiate clinical status groups and may reflect early functional changes preceding cognitive decline.},
}

Humans
Male
Female
*Automobile Driving
Aged
*Geographic Information Systems
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Aged, 80 and over
Markov Chains
Neuropsychological Tests

@article {pmid42071133,
year = {2026},
author = {Gebril, NM and Elettreby, AM and Younis, AH and Moawad, MHED and Hafez, AM and Sayed, GE and Abdelrahman, KM and El-Kot, SM},
title = {From Cerebrospinal Fluid to Blood Draw: Plasma p-Tau217 as a Non-Invasive Biomarker for Alzheimer's Disease: A Fagan Nomogram-Based Meta-Analytic Study.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42071133},
issn = {1559-1182},
mesh = {*Alzheimer Disease/blood/cerebrospinal fluid/diagnosis ; Humans ; *tau Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; *Nomograms ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and is pathologically defined by amyloid-β and tau accumulation. Current diagnostic methods, such as PET imaging and cerebrospinal fluid (CSF) assays, are accurate but invasive, costly, and limited in accessibility. Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a promising blood-based biomarker, but evidence from individual studies remains heterogeneous. We conducted a systematic review and meta-analysis to evaluate the diagnostic performance of plasma p-tau217 for AD. Following PRISMA guidelines, PubMed, Scopus, and Web of Science were searched up to July 2025. Eligible studies included clinical or biomarker-defined AD cohorts that reported plasma p-tau217 accuracy against amyloid or tau positivity or clinical diagnosis. Data on sensitivity, specificity, likelihood ratios, and diagnostic odds ratio (DOR) were extracted. Study quality was assessed using QUADAS-2. Pooled estimates were calculated using a Bayesian bivariate model, and heterogeneity was explored with meta-regression and subgroup analyses. Twenty-seven studies including 19,652 participants were analyzed. Plasma p-tau217 demonstrated high diagnostic accuracy for biomarker-defined AD, with pooled sensitivity of 85.4% (95% posterior intervals [PI]: 81.4-88.7), specificity of 88.0% (95% PI: 85.1-90.6), positive likelihood ratio (PLR) 7.13, negative likelihood ratio (NLR) 0.167, and DOR 42.7. Performance was consistent across amyloid PET and CSF reference standards. Subgroup analyses showed robust accuracy for amyloid positivity (sensitivity 87.3%, specificity 85.5%), tau positivity (sensitivity 84.9%, specificity 93.8%), and clinical AD diagnosis (sensitivity 72.9%, specificity 89.5%). Plasma p-tau217 consistently outperformed other blood biomarkers and correlated with cognitive decline, frailty, and behavioral impairment. Risk of bias was generally low, with no major publication bias detected. This meta-analysis indicates that plasma p-tau217 demonstrates promising diagnostic accuracy for detecting AD pathology across biomarker-defined reference standards. However, heterogeneity across assays, populations, and reference definitions, along with the use of optimized cut-offs in some studies and the limited power of publication-bias assessments, warrant cautious interpretation. Plasma p-tau217 appears well suited as a triage biomarker to guide confirmatory testing, but further large, prospectively designed studies with standardized assays and externally validated thresholds are needed before widespread clinical implementation.},
}

*Alzheimer Disease/blood/cerebrospinal fluid/diagnosis
Humans
*tau Proteins/blood/cerebrospinal fluid
Biomarkers/blood/cerebrospinal fluid
*Nomograms
Phosphorylation

@article {pmid42071158,
year = {2026},
author = {Abuhassan, Q and Saeed, TN and Al-Hussainy, AF and Roopashree, R and Mishra, S and Nanda, A and Mukherjee, G and Rizaev, J and Taher, SG and Alwan, M and Jawad, M and Mushtaq, H},
title = {Viral Mimicry of Alzheimer's Disease: Innate Sensing of Self-Nucleic Acids as a Driver of Glial Senescence.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42071158},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/immunology/virology/metabolism/genetics ; *Immunity, Innate ; Animals ; *Neuroglia/immunology/metabolism ; *Molecular Mimicry ; *Cellular Senescence ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder defined by progressive memory loss and synaptic failure. For decades, therapeutic development has focused on clearing amyloid-beta plaques, yet the repeated clinical failures of this approach necessitate a fundamental paradigm shift toward the brain's immunometabolic landscape. The "Viral Mimicry" hypothesis posits that AD represents a state of sterile autoimmunity where the innate immune system mistakenly identifies self-nucleic acids as viral pathogens. This "ghost war" is ignited by the convergence of metabolic dysfunction and genomic instability: specifically, the leakage of mitochondrial DNA into the cytosol and the epigenetic derepression of ancient retrotransposons (LINE-1, HERVs). These endogenous ligands activate the cGAS-STING cytosolic sensing axis, a pathway that drives a chronic interferon response. Consequently, microglia and astrocytes are transformed into senescent, pro-inflammatory phenotypes that release a toxic Senescence-Associated Secretory Phenotype (SASP), directly fueling synaptic elimination. Crucially, major genetic risk factors, including APOE4 and TREM2 variants, exacerbate this cascade by compromising mitochondrial integrity and lipid metabolism, thereby sensitizing the brain to innate surveillance failure. By reconceptualizing AD as an acquired interferopathy driven by the "enemy within," this framework highlights novel therapeutic targets. Specifically, repurposing Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to block retrotransposition and deploying senolytics to clear dysfunctional glia offer promising strategies to arrest the progression from healthy aging to cognitive decline. This review synthesizes current research on the molecular mechanisms of viral mimicry, detailing the impact of genetic risk factors and evaluating emerging therapeutic interventions targeting this innate immune axis.},
}

Humans
*Alzheimer Disease/immunology/virology/metabolism/genetics
*Immunity, Innate
Animals
*Neuroglia/immunology/metabolism
*Molecular Mimicry
*Cellular Senescence

@article {pmid42071170,
year = {2026},
author = {Tang, C and Yang, J and Lei, X and He, D},
title = {Reply to: Beyond AUC: Advancing clinical interpretability of depression-MRI-machine learning analyses in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71439},
doi = {10.1002/alz.71439},
pmid = {42071170},
issn = {1552-5279},
support = {2021ZD0201801//STI2023-Major Projects/ ; //Key and Dominant Discipline Construction Project of the Health Commission of Guizhou Province/ ; //Guizhou Provincial Science and Technology Support Program Project/ ; LCZX[2025]003//Guizhou Provincial Clinical Medical Research Center Construction Project-Neurological Disease Research/ ; },
}

@article {pmid42071257,
year = {2026},
author = {Richard, JE and Mohammad, A and Lieblich, SE and Go, KA and Wang, S and Rechlin, RK and Splinter, TFL and Barreto, GE and Galea, LAM},
title = {Reproductive history differentially shapes the neural response of middle-aged hAPOEɛ4 female rats to estradiol therapy after a metabolic challenge.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00911-y},
pmid = {42071257},
issn = {2042-6410},
support = {PJT173554/CAPMC/CIHR/Canada ; },
abstract = {BACKGROUND: Advancing age, the APOEɛ4 allele, and female sex are the top nonmodifiable risk factors for Alzheimer's disease (AD). Female-specific experiences, such as parity and hormone therapy (HT) affect aging biomarkers such as metabolism and immune signaling, and may affect AD risk. Estradiol (E2), a component of many HTs, affects cognition and brain health in aging females although studies suggest the effects can vary depending on parity, genotype, and metabolic status which may account for some of the inconsistencies in the literature. We hypothesized that prior parity influences brain and metabolic health, including response to E2, depending on APOE genotype.

METHODS: Middle-aged female (10 month) wildtype (WT) or humanized (h) APOEɛ4 expressing rats, with different reproductive experience (nulliparous or primiparous) were fed a Western (WD) or standard diet (SD) for 2 months. In the second month, rats were given E2 or vehicle (oil) injections daily. Fear associative learning, plasma metabolic hormones, hippocampal inflammatory cytokine expression, and neuroplasticity (neurogenesis, synaptic protein) were assessed.

RESULTS: Females fed a WD gained weight and displayed metabolic dysregulation, regardless of genotype. E2 treatment reduced WD-induced weight gain and reduced metabolic hormones, with stronger effects in WT rats. E2 treatment increased dorsal hippocampal inflammatory cytokine expression selectively in primiparous hAPOEɛ4 females fed a WD. Previous parity increased neurogenesis and reduced certain cytokine expression in the hippocampus of middle-aged WT rats under a SD. Both E2 treatment and previous parity decreased dorsal neurogenesis in hippocampus of hAPOEɛ4 rats. In hAPOEɛ4 females, higher weight was associated with reduced contextual fear memory, an effect driven by primiparous females. In the cued fear conditioning task, hAPOEɛ4 females displayed better cued fear memory than WT, however, WD exposure reduced cued fear memory only in this group. Together, this indicates that diet and weight gain may be more detrimental to associative memory in hAPOEɛ4 females and that E2 treatment has more favourable outcomes in WT rats.

CONCLUSIONS: Previous parity alters how females respond to E2 and metabolic stress in midlife. Primiparous hAPOEɛ4 females were especially vulnerable to the effects of WD and E2, exhibiting more inflammation, impaired memory, and reduced weight-loss. These findings highlight the importance of considering parity and genotype when evaluating midlife metabolic and cognitive risk.},
}

@article {pmid42071322,
year = {2026},
author = {Buttifant, E and Allogmanny, S and Probst, Y},
title = {Investigating Disordered Eating Behaviours Among Individuals Living With Neurodegenerative Disease: A Scoping Review.},
journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association},
volume = {39},
number = {3},
pages = {e70250},
doi = {10.1111/jhn.70250},
pmid = {42071322},
issn = {1365-277X},
mesh = {Humans ; *Feeding and Eating Disorders/etiology/epidemiology/complications ; *Neurodegenerative Diseases/complications/psychology ; *Feeding Behavior/psychology ; Hyperphagia ; Female ; Male ; Alzheimer Disease/complications ; },
abstract = {AIM: Neurodegenerative diseases and disordered eating have become rapidly expanding areas of research. However, research addressing the relationship between the two is lacking.

METHODS: A scoping review guided by the Joanna Briggs Institute methodological framework was completed to synthesise the evidence related to disordered eating behaviours among individuals living with neurodegenerative disease. A systematic search strategy was applied across four scientific databases. A narrative descriptive analysis was conducted to identify key patterns in the studies categorised by the type of eating behaviour. The types of tools used within studies were explored.

RESULTS: Thirty-six evidence sources were included in this review. Overeating-related issues such as hyperphagia were identified (n = 5, 25%) for dementia and Alzheimer's disease-related studies. Appetite-related changes were prevalent across amyotrophic lateral sclerosis (n = 1, 100%) and dementia and Alzheimer's disease-related studies (n = 6, 30%). Food addiction and binge eating were reported in all Parkinson's disease studies (n = 9, 100%), and in one case report for dementia. Eating disorders such as anorexia, bulimia and binge eating disorder were identified in all multiple sclerosis-related studies (n = 6, 100%). Validated and unvalidated tools (53%, n = 19) were used to identify eating behaviours.

CONCLUSIONS: This review revealed reports of disordered eating behaviours among various neurodegenerative disease types. Additional research is required to understand the aetiology and mechanisms behind disordered eating behaviours in these populations. Standardised tools to assess eating behaviours for people living with a neurodegenerative disease are needed. Eating behaviours should be screened upon neurodegenerative disease diagnosis and monitored as part of routine care.},
}

Humans
*Feeding and Eating Disorders/etiology/epidemiology/complications
*Neurodegenerative Diseases/complications/psychology
*Feeding Behavior/psychology
Hyperphagia
Female
Male
Alzheimer Disease/complications

@article {pmid42071824,
year = {2026},
author = {Li, Q and Jing, S and Li, N and Yuan, X and Wang, T},
title = {Causality relationship between 91 inflammatory factors and Alzheimer disease: A bidirectional Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {17},
pages = {e48136},
doi = {10.1097/MD.0000000000048136},
pmid = {42071824},
issn = {1536-5964},
support = {2024439//Chengdu Medical Research Project/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Inflammation/genetics/blood ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; },
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder characterized by amyloid plaque deposition, neurofibrillary tangles, and chronic neuroinflammation. Due to its complexity and difficult-to-treat nature, it has cast a huge shadow over global health. In addition to genetic susceptibility, the development of AD is closely related to systemic inflammation. This study aims to evaluate the association between systemic inflammatory factors and AD through a bidirectional Mendelian randomization (MR) design. Our MR design incorporated aggregated data from extensive genome-wide association studies to investigate the causal relationship between genetically determined systemic inflammatory factors and AD. The MR analysis results identified 9 potential systemic inflammatory regulatory factors: C-X-C motif chemokine 5, interleukin-18 receptor 1, interleukin-6, and tumor necrosis factor, which were associated with an increased risk. Conversely, AD is significantly correlated with 5 circulating inflammatory regulatory factors, namely, tumor necrosis factor-related apoptosis-inducing ligand, stem cell factor, monocyte chemoattractant protein-4, interleukin-5, and cystatin D, which are considered downstream consequences of AD. It is worth noting that our results have, for the first time, clarified the significant roles of inflammatory factors such as cystatin D and monocyte chemoattractant protein-4 in AD, providing new markers and key targets for further exploration of the molecular mechanism and clinical diagnosis and treatment of AD.},
}

Humans
*Alzheimer Disease/genetics/blood
Mendelian Randomization Analysis
Genome-Wide Association Study
*Inflammation/genetics/blood
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide

@article {pmid42072156,
year = {2026},
author = {Wang, Z and Jiang, X and Lin, J and An, R and He, Y and Li, S},
title = {ScFv T1 Protects Against Mitochondrial Damage of SH-SY5Y Cells Caused by Extracellular Tau Aggregates.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/antiox15040515},
pmid = {42072156},
issn = {2076-3921},
support = {32071222//the National Natural Science Foundation of China/ ; 31570756//the National Natural Science Foundation of China/ ; },
abstract = {Mitochondria are essential organelles that perform irreplaceable functions in neurons. The degeneration of neurons in Alzheimer's disease (AD) is associated with mitochondrial damage, and Tau pathology represents a significant pathogenic factor in AD. However, the relationship between Tau and mitochondrial dysfunction during neuronal degeneration remains unclear. In this study, we investigated the effects and mechanisms by which extracellular Tau aggregates induce neuronal mitochondrial damage and dysfunction. The results showed that extracellular Tau aggregates lead to structural damage of mitochondria in SH-SY5Y cells and disrupt mitochondrial homeostasis. Extracellular Tau aggregates can also cause mitochondrial oxidative stress and inhibit oxidative phosphorylation in SH-SY5Y cells. Concurrently, extracellular Tau aggregates promote neuronal death through an increase in cytochrome C, mtDNA leakage and activation of the cGAS/STING pathway. We also explored the effects of a single-chain variable fragment antibody (scFv T1) and found that scFv T1 alleviated mitochondrial damage and dysfunction by inhibiting the formation of Tau aggregates. These findings suggest that targeting Tau pathology may be crucial to address neuronal mitochondrial impairment and that reduction of the toxicity associated with extracellular Tau aggregates could help slow Tau pathology progression.},
}

@article {pmid42072160,
year = {2026},
author = {Tng, TJW and Cheah, IK and Halliwell, B and Lim, KL},
title = {Potential Protection Against Parkinson's Disease by Ergothioneine-Nature's Multifactorial Neuroprotectant.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/antiox15040519},
pmid = {42072160},
issn = {2076-3921},
support = {#023643-00001//Ministry of Education/ ; },
abstract = {The use of neuroprotective nutraceuticals as a strategy against neurodegenerative diseases such as Parkinson's disease (PD) has gained considerable traction in recent years. In this review, we highlight ergothioneine (ET)-a naturally occurring thiol/thione derivative abundant in mushrooms-as a promising candidate, given its long half-life, blood-brain barrier penetration, and high bioavailability. Numerous population studies have linked low blood ET levels with increased risk and progression of neurological and other age-related disorders in humans, suggesting that dietary ET may confer neuroprotective benefits. Supporting this, several studies have demonstrated the efficacy of ET treatment in reducing PD-associated molecular damage across various pre-clinical models such as C. elegans, Drosophila, rodent models and human neuronal cultures, leading to marked improvements in disease phenotypes. Here, we summarize some of the proposed mechanisms by which ET may exert neuroprotection in PD, including the reduction of protein aggregation, enhancement of mitochondrial function, mitigation of oxidative stress, and attenuation of apoptosis and neuroinflammation. We also highlight recent clinical trials demonstrating the safety and potential efficacy of ET and propose future research to facilitate the translation of ET into the clinic.},
}

@article {pmid42072161,
year = {2026},
author = {Tramutola, A and Lanzillotta, C and Di Domenico, F and Barone, E and Perluigi, M},
title = {Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/antiox15040520},
pmid = {42072161},
issn = {2076-3921},
abstract = {Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer's disease (AD). Beyond gene-dosage imbalance, trisomy 21 induces widespread transcriptional, metabolic, and proteomic remodeling that establishes a chronic state of proteotoxic and oxidative stress from early development. Increasing evidence identifies DS as a disorder of proteostasis network failure, in which sustained translational pressure, redox disequilibrium, and degradation pathway insufficiency progressively erode cellular resilience. In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and excessive reactive oxygen species production, and impaired antioxidant responses create a highly vulnerable intracellular environment. Concomitantly, degradation systems become compromised: proteasomal catalytic activity declines, ubiquitin-dependent signaling is remodeled, and chronic mTOR hyperactivation suppresses autophagic and mitophagic flux. The coordinated impairment of the ubiquitin-proteasome system and autophagy establish a feed-forward cycle of proteotoxic accumulation and redox amplification. Within this framework, Alzheimer-like neuropathology in DS emerges not solely from amyloid precursor protein triplication but as the late manifestation of decades-long proteostasis exhaustion. Therapeutic strategies aimed at restoring global proteostasis and redox balance may therefore represent a more effective systems-level approach to mitigating neurodegeneration in DS.},
}

@article {pmid42072300,
year = {2026},
author = {Zawadzka, M and Rydzek, J and Lizon, J and Krupa, Z and Wrona, J and Woźniak, S},
title = {Cellular Senescence in Neurodegeneration: From Cell Types to Therapeutic Opportunities.},
journal = {Biomedicines},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biomedicines14040758},
pmid = {42072300},
issn = {2227-9059},
abstract = {Neurodegenerative diseases of the central nervous system, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, represent a growing health challenge in ageing populations. Among the mechanisms underlying these disorders, increasing attention has been directed toward the role of cellular senescence. This process, triggered by chronic cellular and oxidative stress as well as DNA damage, leads to irreversible cell-cycle arrest and the development of the senescence-associated secretory phenotype (SASP). Within the central nervous system, the accumulation of senescent cells induces chronic inflammation, blood-brain barrier disruption, and progression of neurodegenerative processes. In this review, we present current evidence regarding the mechanisms of cellular senescence in the central nervous system, with particular emphasis on the role of SASP in neuroinflammation, vascular dysfunction, and neural tissue damage. Experimental and clinical data supporting the involvement of cellular senescence in the pathogenesis of Alzheimer's disease, Parkinson's disease, and multiple sclerosis are discussed. The review also covers methods for identifying senescent cells in the brain, including molecular marker-based approaches and machine learning-based tools. Importantly, we discuss the methodological limitations of commonly used senescence markers, such as their limited specificity and the risk of false-positive detection, particularly in the heterogeneous cellular environment of the central nervous system. Strategies to improve detection reliability discussed in this review include the use of multimarker signatures, analysis of SASP components using qRT-PCR and ELISA, as well as transcriptomic approaches such as RNA sequencing and single-cell RNA sequencing. Furthermore, we analyze therapeutic strategies targeting senescent cells-senolytics, senomorphics, and SASP modulation-together with their limitations and associated clinical challenges. The collected evidence indicates that precise characterization of senescent cell populations in the brain is essential for the development of disease-modifying therapies for neurodegenerative disorders.},
}

@article {pmid42072302,
year = {2026},
author = {Omar, SH and Ghani, MA},
title = {Olive Components (Biophenols or Polyphenols) in Neurodegenerative Disease Models and Clinical Studies: A Systematic Review of Evidence and Translational Barriers.},
journal = {Biomedicines},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biomedicines14040761},
pmid = {42072302},
issn = {2227-9059},
abstract = {Introduction: Olives have been used in traditional Mediterranean medicine for thousands of years to address the causes of inflammation, ageing and cognitive health. Traditional preparations of olive include olive oil and olive leaf extract, which are major components of diets that contribute to maintaining cognitive function and reducing neurodegenerative disease risk. Aims of the study: This systematic review aimed to synthesise experimental and limited human evidence on olive biophenols in neurodegenerative disease models, identify the most studied compounds, characterise their mechanisms of action, and evaluate key translational barriers. Materials and methods: Following PRISMA 2020 guidelines and registered with PROSPERO (CRD420251252252), primary studies investigating the effects of well-characterised olive biophenols in neurodegenerative relevant in vitro, in vivo, or human models were systematically reviewed. Each study was assessed for its design, experimental model, mechanistic outcomes and reported limitations. Risk of bias was evaluated using validated tools (SYRCLE/OHAT/ToxR) appropriate for preclinical and experimental study designs. Results: Among the 25 studies, 7 (28.0%) examined oleuropein or oleuropein aglycone, 10 (40.0%) focused on hydroxytyrosol or its derivatives, and 9 (36.0%) investigated oleocanthal. Most studies employed in vivo animal models (57.7%), predominantly transgenic mouse models of AD and toxin-induced PD models. Oleuropein-based studies reported inhibition of amyloid-β and α-synuclein aggregation with behavioural improvements. Hydroxytyrosol primarily exerted antioxidant and anti-inflammatory effects with modest cognitive benefits. Oleocanthal showed the most consistent anti-amyloid and anti-tau activity, including enhanced amyloid-β clearance across the blood-brain barrier. Most studies show a moderate risk of bias due to incomplete reporting, randomisation and blinding. Conclusions: Olive biophenols demonstrate consistent neuroprotective effects in preclinical models; however, translation to clinical application remains limited by pharmacokinetic constraints, methodological heterogeneity, and insufficient human evidence.},
}

@article {pmid42072320,
year = {2026},
author = {Mikhailov, IG and Mikhailova, MS and Baklashov, AD and Ponamareva, PS and Shumilova, SN and Shuvaev, AN and Belozor, OS and Shuvaev, AN},
title = {Intranasal Formaldehyde Exposure Induces RAGE-Mediated Alteration of the ADAM10/BACE1 Expression Balance and Amyloid Deposition.},
journal = {Biomedicines},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biomedicines14040779},
pmid = {42072320},
issn = {2227-9059},
support = {24-75-00034//Russian Science Foundation/ ; },
abstract = {Background: Alzheimer's disease (AD) remains an incurable disorder with severe clinical consequences. The type 3 diabetes hypothesis posits that AD may constitute a neuroendocrine disorder driven by disrupted insulin and insulin-like growth factor signaling. Amyloid pathogenesis in AD is characterized by the accumulation of beta-amyloid (Aβ) monomers, their subsequent oligomerization, and amyloid deposition. One of the causes of Aβ accumulation is disruption of amyloid precursor protein (APP) processing due to imbalance in ADAM10 and BACE1 expression. In recent years, increasing attention has been devoted to investigating the role of environmental factors in AD pathogenesis. The receptor for advanced glycation end products (RAGE) serves as a key molecular link between environmental exposure and neuroinflammatory pathology. Formaldehyde (FA) is one of the most widespread environmental pollutants. Its involvement in amyloid plaque formation has been previously reported; however, the molecular mechanisms underlying this process remain insufficiently understood. Moreover, most available data are based on prolonged FA exposure, whereas industrial FA emissions are often short-term. The objective of this study was to determine whether brief intranasal administration of FA, modeling episodic industrial pollution, induces RAGE-mediated neuroinflammation and amyloid deposition in CD1 mice. Methods: Mice received intranasal FA at environmentally relevant 0.02 mg/day or 0.2 mg/day doses for seven days; an additional group was co-treated with insulin. Cognitive function was assessed using passive avoidance (PA) and radial arm maze (RAM) tests, and synaptic plasticity was evaluated by electrophysiology. Hippocampal tissue was analyzed for RAGE expression, ADAM10/BACE1 gene balance, Aβ42 monomer levels, and amyloid deposits using optimized Thioflavin-S (Th-S) staining. Results: We observed cognitive decline in mice receiving intranasal FA administration. Elevated blood glucose levels were also observed following intranasal FA exposure. Sustained impairment of glucose metabolism led to overexpression of the RAGE in the hippocampus. There was also an imbalance of ADAM10 and BACE1 expression in the hippocampus. This was caused by overexpression of RAGE, as the enhanced interaction of the ligand and RAGE is a key factor disrupting this balance. Finally, Th-S staining confirmed amyloid deposition in mice subjected to intranasal FA exposure. Conclusions: This study provides new insights into the RAGE-mediated mechanisms by which FA contributes to the pathogenesis of AD.},
}

@article {pmid42072370,
year = {2026},
author = {Kim, ME and Lee, JS},
title = {IL-10-STAT3-Dependent Transcriptional Regulation in Microglia: Alzheimer's Disease and Neuroinflammation.},
journal = {Biomedicines},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biomedicines14040826},
pmid = {42072370},
issn = {2227-9059},
abstract = {Interleukin-10 (IL-10) is a key immunoregulatory cytokine that suppresses inflammatory gene transcription in myeloid cells through signal transducer and activator of transcription 3 (STAT3). In Alzheimer's disease and neuroinflammation, microglia express IL10ra and exhibit STAT3 Tyr705 phosphorylation following IL-10 stimulation, indicating IL-10 receptor-dependent STAT3 activation. Recent studies demonstrate that IL-10 induces promoter-selective STAT3-dependent transcriptional regulation in microglia through chromatin-associated mechanisms, whereas gp130-dependent cytokines activate STAT3 to induce transcription of defined target genes, including Socs3 and Ccl5. Following IL-10 receptor activation, STAT3 binds regulatory regions of inflammatory genes, including Il1b, Tnf, Il6, and Nlrp3, with reduced RNA polymerase II and NF-κB binding. IL-10-dependent transcriptional repression involves formation of a nuclear SHIP1-STAT3 complex, localization of histone deacetylase (HDAC)1 and HDAC2 to H3K4me1-enriched enhancer regions, reduced H3K27ac, and decreased chromatin accessibility at regulatory regions of inflammatory genes. IL-10-activated STAT3 induces Socs3, which regulates JAK1 and TYK2 activity and STAT3 phosphorylation. Impairment of IL-10 receptor signaling in microglia is associated with increased inflammatory gene expression, enhanced inflammasome-related transcription, demyelination, and amyloid accumulation. This review focuses on IL-10-STAT3-dependent transcriptional regulation in microglia, including receptor signaling, chromatin-associated mechanisms, and disease-associated gene expression in Alzheimer's disease and neuroinflammation.},
}

@article {pmid42072403,
year = {2026},
author = {Shajahan, SR and Hamid, N and Okunsai, B and Shari, N and Ramli, MDC},
title = {Microbiota-Gut-Brain Axis in Alzheimer's Disease: Linking Oxidative Stress, Mitochondrial Dysfunction and Amyloid Pathology-A Systematic Review.},
journal = {Biomedicines},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biomedicines14040860},
pmid = {42072403},
issn = {2227-9059},
abstract = {Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, and mitochondrial dysfunction. Emerging evidence indicates that the gut microbiota plays a critical role in modulating neuroinflammatory, and metabolic pathways involved in AD pathogenesis through the microbiota-gut-brain axis. Objective: This systematic review aims to comprehensively evaluate the role of the microbiota-gut-brain axis in Alzheimer's disease, with a particular focus on its mechanistic links to oxidative stress, mitochondrial dysfunction, and amyloid pathology, as well as its therapeutic potential. Methodology: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases, focusing on studies evaluating gut microbiota composition, metabolomic changes, oxidative stress markers, mitochondrial activity, and therapeutic interventions in AD models and patients. Results: Altered gut microbial composition in AD is associated with increased pro-inflammatory taxa (Escherichia-Shigella, Bacteroides) and depletion of short-chain fatty acid (SCFA) producing bacteria (Faecalibacterium, Roseburia). Dysbiosis contributes to systemic inflammation, disrupted intestinal permeability, and microglial activation, leading to oxidative damage and mitochondrial impairment in neurons. Preclinical and clinical studies indicate that probiotics, prebiotics, and fecal microbiota transplantation can restore redox balance, reduce neuroinflammation, and improve cognitive outcomes. Multi-omics and AI-based models are emerging as tools for identifying microbiome-derived biomarkers for early AD detection. Conclusion: The gut microbiota-mitochondria-oxidative stress axis represents a promising therapeutic target in Alzheimer's disease. Future research should focus on longitudinal human studies, standardized microbial profiling, and personalized microbiome-based interventions to translate these mechanistic insights into clinical benefit.},
}

@article {pmid42072570,
year = {2026},
author = {Dong, L},
title = {A Unified Information Bottleneck Framework for Multimodal Biomedical Machine Learning.},
journal = {Entropy (Basel, Switzerland)},
volume = {28},
number = {4},
pages = {},
doi = {10.3390/e28040445},
pmid = {42072570},
issn = {1099-4300},
support = {R01CA309499/CA/NCI NIH HHS/United States ; },
abstract = {Multimodal biomedical machine learning increasingly integrates heterogeneous data sources (including medical imaging, multi-omics profiles, electronic health records, and wearable sensor signals) to support clinical diagnosis, prognosis, and treatment response prediction. Despite strong empirical performance, most existing multimodal systems lack a principled theoretical foundation for understanding why fusion improves prediction, how information is distributed across modalities, and when models can be trusted under incomplete or shifting data. This paper develops a unified information-theoretic framework that formalizes multimodal biomedical learning as an information optimization problem. We formulate multimodal representation learning through the information bottleneck principle, deriving a variational objective that balances predictive sufficiency against informational compression in an architecture-agnostic manner. Building on this foundation, we introduce information-theoretic tools for decomposing modality contributions via conditional mutual information, quantifying redundancy and synergy, and diagnosing fusion collapse. We further show that robustness to missing modalities can be cast as an information consistency problem and extend the framework to longitudinal disease modeling through transfer entropy and sequential information bottleneck objectives. Applications to multimodal foundation models, uncertainty quantification, calibration, and out-of-distribution detection are developed. Empirical case studies across three biomedical datasets (TCGA breast cancer multi-omics, TCGA glioma clinical-plus-molecular data, and OASIS-2 longitudinal Alzheimer's data) show that the framework's key quantities are computable and interpretable on real data: MI decomposition identifies modality dominance and redundancy; the VMIB traces a compression-prediction tradeoff in the information plane; entropy-based selective prediction raises accuracy from 0.787 to 0.939 at 50% coverage; transfer entropy reveals stage-dependent modality influence in disease progression; and pretraining/adaptation diagnostics distinguish efficient from wasteful fine-tuning strategies. Together, these results develop entropy and mutual information as organizing principles for the design, analysis, and evaluation of multimodal biomedical AI systems.},
}

@article {pmid42072614,
year = {2026},
author = {Ferreon, JC and Choi, KJ and Quan, MD and Tsoi, PS and Ferreon, CC and Coskun, U and Liao, SJ and Ferreon, ACM},
title = {Modulation of Biomolecular Aggregate Morphology and Condensate Infectivity.},
journal = {Biomolecules},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/biom16040492},
pmid = {42072614},
issn = {2218-273X},
support = {R01 GM122763/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Protein Aggregates ; *Heterogeneous Nuclear Ribonucleoprotein A1/chemistry/metabolism/genetics ; Amyloid/metabolism/chemistry ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Biomolecular Condensates/chemistry/metabolism ; Prions/metabolism/chemistry ; *Protein Aggregation, Pathological/metabolism ; },
abstract = {Neurodegenerative diseases feature diverse pathological protein aggregates, including Lewy bodies in Alzheimer's disease (AD) and skein-like filaments in amyotrophic lateral sclerosis (ALS). The physical mechanisms underlying this morphological diversity remain unclear. Here, we demonstrate that aggregation of the prion-like domain of hnRNPA1 (A1PrD), implicated in AD and ALS, is driven by solution composition and phase transition dynamics. Utilizing 3D timelapse and fluorescence lifetime imaging microscopy, we show that solution conditions modulate phase separation, gelation, and fibrillation, resulting in distinct structures such as fibril, gel, and starburst morphologies. Homotypic and heterotypic interactions between A1PrD and RNA were observed to shift the balance between pathological and physiological condensates. Importantly, amyloid-rich starbursts displayed prion-like infection capabilities toward amyloid-poor condensates. Our findings highlight how the interplay between solution composition and kinetic balances of liquid-liquid phase separation, gelation, and fibrillation shapes the diverse pathological aggregate morphologies characteristic of neurodegenerative diseases.},
}

Humans
*Protein Aggregates
*Heterogeneous Nuclear Ribonucleoprotein A1/chemistry/metabolism/genetics
Amyloid/metabolism/chemistry
Alzheimer Disease/metabolism/pathology
Amyotrophic Lateral Sclerosis/metabolism/pathology
*Biomolecular Condensates/chemistry/metabolism
Prions/metabolism/chemistry
*Protein Aggregation, Pathological/metabolism

@article {pmid42072639,
year = {2026},
author = {Kocurova, G and Svabenska, Z and Klaschka, J and Bartos, A and Ricny, J},
title = {Plasma Autoantibodies Against Neurodegeneration-Related Antigens in Dementia and Elevated Chi3Li Autoantibodies in Mild Cognitive Impairment.},
journal = {Biomolecules},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/biom16040518},
pmid = {42072639},
issn = {2218-273X},
support = {CZ.01.1.02/0.0/0.0/17_176/0015497//Operational Program Entrepreneurship and Innovation for Competitiveness of Ministry of Industry and Trade: Utilisation of industrial biotechnology methods for differential diagnostic of neurological diseases/ ; COOPERATIO 38//Institutional support of research and creative activities at Charles University./ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Cognitive Dysfunction/blood/immunology ; *Autoantibodies/blood/immunology ; *Dementia/blood/immunology ; Aged, 80 and over ; Middle Aged ; Biomarkers/blood ; Neurodegenerative Diseases/immunology/blood ; alpha-Synuclein/immunology ; Membrane Glycoproteins ; Receptors, Immunologic ; },
abstract = {Systemic autoimmunity plays an important role in pathogenesis of neurodegenerative diseases. The objective of our study was to explore the seroprevalence of naturally occurring autoantibodies (Aabs) targeting a panel of 14 antigens broadly involved in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, frontotemporal dementia, and vascular dementia. Commonly associated proteins with underlying neuronal pathology of the brain include amyloid-beta (Aβ), tau, alpha-synuclein (α-syn), TDP-43, and FUS. Proteins associated with glial and astrocytic involvement-TREM2 and Chi3Li; proteins related to myelin damage and axonal degeneration-light neurofilaments (NFL), myelin basic protein (MBP); synaptic loss reflected by neurogranin (NRGN), a marker of neuronal injury-neuron specific enolase (NSE); and markers of disturbed calcium homeostasis-VSNL1 and neuroinflammation-MCP-1. Presence and levels of plasma IgG against these antigens were examined using enzyme-linked immunosorbent assay (ELISA) method in patients with dementia, patients with mild cognitive impairment (MCI), and healthy age-matched controls. Aabs against all selected antigens were detected across all groups, including healthy control, with varied seroprevalence levels. For the first time, we report the presence of anti-FUS, anti-TREM2, anti-NRGN, anti-VSNL1, anti-NSE, and anti-MCP1 Aabs. Elevated anti-Chi3Li Aabs in individuals with MCI indicate a disease-associated immune signature linked to early neurodegenerative processes. Overall, these results provide evidence of systemic immune activation accompanying neurodegeneration, underscore the complexity of immune involvement, and highlight the importance of targeting multiple pathological pathways in future immunomodulatory strategies.},
}

Humans
Female
Male
Aged
*Cognitive Dysfunction/blood/immunology
*Autoantibodies/blood/immunology
*Dementia/blood/immunology
Aged, 80 and over
Middle Aged
Biomarkers/blood
Neurodegenerative Diseases/immunology/blood
alpha-Synuclein/immunology
Membrane Glycoproteins
Receptors, Immunologic

@article {pmid42072691,
year = {2026},
author = {Fu, T and Shi, Y and Yang, Z and Zhou, J and Huang, L and Fu, Y and Xiong, W},
title = {Variecolactone, a Natural PDE4 Inhibitor from Marine-Derived Talaromyces sp. ZSD-1, Alleviates Amyloid-β Accumulation and mtDNA Dyshomeostasis via cAMP-PKA-CREB Signaling Pathway.},
journal = {Biomolecules},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/biom16040570},
pmid = {42072691},
issn = {2218-273X},
support = {825QN283//Hainan Provincial Natural Science Foundation of China/ ; 82404601//National Natural Science Foundation of China/ ; 22577021//Natural Science Foundation of China/ ; },
mesh = {*Amyloid beta-Peptides/metabolism ; *Phosphodiesterase 4 Inhibitors/pharmacology/chemistry ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Humans ; *DNA, Mitochondrial/metabolism/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Mitochondria/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β deposition, neuroinflammation, and mitochondrial dysfunction. Phosphodiesterase 4 (PDE4), a key regulator of cyclic nucleotides in neurons, represents a promising therapeutic target for AD. In this study, we performed a PDE4 inhibition-guided screen of an in-house marine natural product library derived from marine fungi, leading to the identification of a sesterterpenoid variecolactone (VLT) as a potent PDE4 inhibitor. VLT exhibited selective PDE4D inhibition (IC50 = 2.302 μM) with minimal activity against other PDE subtypes. Further mechanical investigation revealed that VLT treatment elevated cAMP and p-CREB levels, reduced amyloid-β (Aβ) accumulation, promoted synaptic function, and ameliorated mitochondrial fragmentation, along with mtDNA homeostasis in the AD cell model. Moreover, under conditions of mtDNA depletion or Drp1 overexpression, VLT exerted neuroprotective effects and maintained mtDNA homeostasis via the cAMP-PKA-CREB signaling pathway. These results demonstrate that PDE4 inhibition by VLT represents a promising therapeutic strategy for AD and related neurodegenerative disorders.},
}

*Amyloid beta-Peptides/metabolism
*Phosphodiesterase 4 Inhibitors/pharmacology/chemistry
Signal Transduction/drug effects
Cyclic AMP/metabolism
Cyclic AMP-Dependent Protein Kinases/metabolism
Cyclic AMP Response Element-Binding Protein/metabolism
Humans
*DNA, Mitochondrial/metabolism/genetics
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism
Alzheimer Disease/drug therapy/metabolism
Animals
Mitochondria/drug effects/metabolism

@article {pmid42072714,
year = {2026},
author = {Verano, AB and Sampietro, A and Mallo-Abreu, A and Spagnuolo, R and Pérez, B and Bartolini, M and Loza, MI and Brea, J and Juárez-Jiménez, J and Sabate, R and Galdeano, C and Muñoz-Torrero, D},
title = {Synthesis and Biological Profiling of New 1,2,3,4-Tetrahydrobenzo[h]naphthyridine-Based Hybrids as Dual Inhibitors of β-Amyloid and Tau Aggregation with Anticholinesterase Activity.},
journal = {Biomolecules},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/biom16040593},
pmid = {42072714},
issn = {2218-273X},
support = {PID2023-147004OB-I00//MICIU/AEI/10.13039/501100011033/ ; },
mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *tau Proteins/metabolism/antagonists & inhibitors/chemistry ; Humans ; *Naphthyridines/chemistry/pharmacology/chemical synthesis ; Protein Aggregates/drug effects ; Animals ; Acetylcholinesterase/metabolism ; Structure-Activity Relationship ; Cell Survival/drug effects ; },
abstract = {DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids 16 and 17, with similar or even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies.},
}

*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry
*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
*tau Proteins/metabolism/antagonists & inhibitors/chemistry
Humans
*Naphthyridines/chemistry/pharmacology/chemical synthesis
Protein Aggregates/drug effects
Animals
Acetylcholinesterase/metabolism
Structure-Activity Relationship
Cell Survival/drug effects

@article {pmid42072716,
year = {2026},
author = {Strużyńska, L and Adamiak, K and Sidoryk-Węgrzynowicz, M},
title = {Tau and β-Amyloid Relevant Pathology as a Central Therapeutic Target in Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/biom16040595},
pmid = {42072716},
issn = {2218-273X},
support = {3/2026//Funds from statutable funds were provided by the Ministry of Education and Science for the Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; Biomarkers/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, responsible for approximately 60-70% of cases globally. AD is a gradually progressive neurodegenerative disorder that is characterized by widespread deposition of β-amyloid (Aβ) plaques, followed by aggregation of tau protein in the neocortex, neurodegeneration, and cognitive decline. Within these complex pathological interactions, Aβ and tau proteins, together with astrogliosis, neuroinflammation, and other factors, play a key role in the development of clinical AD. Accumulating evidence indicates that the formation of protein oligomers, followed by their aggregation into pathological fibrils, constitutes an early and critical step in the pathogenesis of the disease. Specific pathological proteins are often treated as biomarkers of particular diseases because their presence, concentration, or altered structure reflects an underlying disease process. It is well established that the Aβ and tau proteins are the key hallmarks of AD, and their mutual interaction may significantly influence the pathology of the disease. Early diagnosis is crucial for maximizing the therapeutic benefits of currently available symptomatic treatments, which can alleviate symptoms and modestly delay clinical deterioration in patients with AD. This review highlights the mechanisms involved in protein-dependent neurodegeneration and describes both traditional and novel approaches for the cure of AD. The most important aspect of this publication is the integration of the two key proteins: Aβ and tau, and the resulting shift toward a new therapeutic approach.},
}

Humans
*Alzheimer Disease/metabolism/pathology/drug therapy
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Animals
Biomarkers/metabolism

@article {pmid42072789,
year = {2026},
author = {Chung, WK and Kim, HM and Lee, MB and Kim, K and Kwon, OI and Yoo, YJ and Rhee, HY and Jahng, GH},
title = {Evaluation of Low-Dose Radiation Treatment Effects Using Conductivity, Diffusivity, and Brain Tissue Volumes Treated in Patients with Mild Alzheimer's Disease: Exploratory Investigation.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/diagnostics16081163},
pmid = {42072789},
issn = {2075-4418},
support = {RS-2024-00335770//National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT/ ; A21IP11//Korea Hydro & Nuclear Power Co. Ltd/ ; },
abstract = {Purpose: No prior clinical studies have quantitatively evaluated the effect of low-dose radiation therapy (LDRT) on Alzheimer's disease (AD) brain changes using multi-modal MRI. This study examined the feasibility of using conductivity, diffusion, and brain tissue volume measures to detect treatment effects in patients with AD receiving LDRT. Methods: Nine patients with mild AD were enrolled in three groups. Three patients in each group were assigned to the control group (0 cGy) and the treated groups [24 cGy/6 fractions (4 cGy for each fraction) and 300 cGy/6 fractions (50 cGy for each fraction)]. Conductivity, diffusivity, and brain tissue volume were acquired at baseline and 6 months post-treatment and were evaluated to assess within-group MRI changes and evaluate associations between MRI measures and Mini-Mental State Examination (MMSE) scores. Results: Region-of-interest (ROI) analyses identified substantial changes in high-frequency conductivity (HFC) (e.g., left insula), cerebrospinal fluid (CSF) volumes (e.g., anterior cingulate, limbic regions), and diffusion tensor imaging (DTI) metrics, such as axial diffusivity (AxD) and fractional anisotropy (FA), in fusiform, thalamic, hippocampal, and occipital areas. Correlation analysis showed strong associations between MRI measures and cognition, most notably HFC in the left fusiform gyrus (r = 0.843, p = 0.0043) after treatment. Diffusion indices across multiple regions also showed significant positive or negative correlations with MMSE. Conclusions: This exploratory clinical study demonstrates that LDRT induces measurable physiological and microstructural alterations in the brain detectable via conductivity and diffusion MRI. Conductivity emerged as the sensitive biomarker, showing strong cognitive correlations. These exploratory findings suggest that multi-modal quantitative MRI can serve as an effective tool for evaluating treatment response in clinical LDRT for AD.},
}

@article {pmid42073016,
year = {2026},
author = {Quansah, M and David, MA and Martins, R and El-Omar, E and Aliberti, SM and Capunzo, M and Jensen, SO and Tayebi, M},
title = {Correction: Quansah et al. The Beneficial Effects of Lactobacillus Strains on Gut Microbiome in Alzheimer's Disease: A Systematic Review. Healthcare 2025, 13, 74.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/healthcare14080974},
pmid = {42073016},
issn = {2227-9032},
abstract = {In the original publication [...].},
}

@article {pmid42073390,
year = {2026},
author = {Hossain, R and Surinkaew, S and Sompol, P and Bastaki, NK and Jafrin, R and Sekeroglu, N and Tangpong, J},
title = {Mapping the Polar Neuro-Interactome of Garcinia mangostana Against the AD-PD-ALS Nexus.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/life16040580},
pmid = {42073390},
issn = {2075-1729},
support = {WU69203//Walailak University under the New Researcher Development scheme/ ; },
abstract = {Background/Objectives: Neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis (ALS) share common molecular pathways, including neuroinflammation and oxidative stress, which complicate the effectiveness of single-target treatments. Garcinia mangostana L. (mangosteen) has shown neuroprotective properties, but previous studies focused on lipophilic xanthones, which have poor bioavailability and uncertain blood-brain barrier permeability. Methods: In the current study, polar metabolites from G. mangostana peel aqueous extract (GMPE) were assessed for potential multi-target interactions via UHPLC-QTOF-MS-based metabolomics, systems pharmacology, and molecular docking analysis. Further, in silico ADMET screening and network-based analyses assessed for overlap between GMPE compounds and genes associated with neurodegeneration (AD, PD, ALS). Results: Analysis of genes linked to AD, PD, and ALS revealed 121 common molecular targets influenced by GMPE metabolites. Network and enrichment analyses indicated that the compounds derived from GMPE may be involved in common pathways related to oxidative stress, neuroinflammation, and neuronal survival. Molecular docking analyses suggest that selected metabolites are likely to exhibit moderate binding affinities to their respective protein targets. Conclusions: The results presented in this study provide evidence that GMPE may possess potential multi-target interactions within common neurodegenerative pathways. However, since the data are based on computational and predictive approaches, these results should be considered hypothesis-generating and warrant further experimental validation.},
}

@article {pmid42073888,
year = {2026},
author = {Seda, A and Mitova, E and Stuckey, AL and Berman, SL},
title = {The Roles of Empathy, Proximity, and Identity in Alzheimer's Disease Stigma.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/bs16040525},
pmid = {42073888},
issn = {2076-328X},
abstract = {Stigma toward individuals with Alzheimer's Disease (AD) can have significant social and psychological consequences, yet research on its contributing factors to stigmatizing attitudes remain limited. The current study represents a novel investigation into stigma toward individuals with AD, a population that has been largely overlooked in studies of stigmatization. The present study aimed to examine psychosocial predictors of AD stigma, focusing on empathy, moral identity, identity distress, and proximity, with individuals with AD as a potential protective factor. A sample of undergraduate students (N = 419) completed self-report measures assessing these constructs. Empathy was the strongest predictor of AD stigma, negatively related to stigmatizing attitudes and fully mediating the relationship between moral identity internalization and stigma. In contrast, identity distress was linked to higher stigma, both directly and indirectly through its negative association with empathy. Proximity to someone with AD was also associated with lower stigma, suggesting that proximity may promote more positive attitudes. These findings highlight the possible central role of empathy in mitigating stigma and suggest that interventions fostering empathic concern, alongside addressing identity-related distress, may help mitigate negative perceptions of individuals with AD.},
}

@article {pmid42073986,
year = {2026},
author = {Keskinoz, EN and Footohi, G and Celik, M and Acar, D and Ozgun, G and Elmas, MA and Yavuz, İ and Ada, E and Sari, E and Ay, B and Unal, MC and Ulus, İH and Arbak, S and Suyen, G and Oz-Arslan, D},
title = {Effects of UMP, Choline, and Fish Oil on Synaptic Integrity and Motor Coordination in an Alzheimer's Disease Mouse Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083342},
pmid = {42073986},
issn = {1422-0067},
support = {3501 - Career Development Program, Grant No: 219S307//Scientific and Technological Research Council of Turkey/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology/drug therapy/pathology ; Disease Models, Animal ; Mice ; *Choline/pharmacology/administration & dosage ; Mice, Transgenic ; Female ; *Fish Oils/pharmacology/administration & dosage ; *Synapses/drug effects/metabolism/pathology ; Hippocampus/metabolism/drug effects/pathology ; Synaptophysin/metabolism ; Disks Large Homolog 4 Protein/metabolism ; Male ; Pregnancy ; Dietary Supplements ; },
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive synaptic dysfunction, axonal pathology, and cognitive decline, with the hippocampal circuits showing particular vulnerability during disease progression. However, early-life nutritional interventions may influence long-term synaptic resilience. In this study, we investigated the long-term effects of prenatal and lactational supplementation with choline, UMP, and fish oil in the 5XFAD mouse model. To this end, hippocampal synaptic and axonal pathology was assessed at 3, 6, and 9 months using Western blotting and immunofluorescence to measure synaptophysin, PSD-95, and neurofilament medium chain (NF-M), alongside a multidimensional behavioral battery that evaluated cognitive, affective, motor, and sensory outcomes. Results showed that early-life supplementation did not significantly improve the learning performance decline, increase nociception, or reverse changes in anxiety behavior in transgenic mice. However, it attenuated synaptic decline in transgenic animals by partially preserving synaptophysin and PSD-95 levels and reducing NF-M elevations. These molecular effects were accompanied by selective behavioral modulation, including preserved learning dynamics, altered anxiety-like behavior, and delayed nociceptive hypersensitivity, while late-stage motor impairments remained largely unaffected. Overall, prenatal and lactational supplementation produced modest, age-dependent effects on synaptic markers and partially prevented neurodegenerative progression in the 5XFAD model.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology/drug therapy/pathology
Disease Models, Animal
Mice
*Choline/pharmacology/administration & dosage
Mice, Transgenic
Female
*Fish Oils/pharmacology/administration & dosage
*Synapses/drug effects/metabolism/pathology
Hippocampus/metabolism/drug effects/pathology
Synaptophysin/metabolism
Disks Large Homolog 4 Protein/metabolism
Male
Pregnancy
Dietary Supplements

@article {pmid42073997,
year = {2026},
author = {Rafique, A and Junaid, A and Bakovic, M},
title = {Impact of Oxidative Stress-Driven Ferroptosis in Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083353},
pmid = {42073997},
issn = {1422-0067},
support = {APP465536/CAPMC/CIHR/Canada ; },
mesh = {*Ferroptosis ; Humans ; *Oxidative Stress ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Lipid Peroxidation ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Ferroptosis is an iron-dependent cell death driven by lipid peroxidation and failure of cellular antioxidant defenses. It is triggered by oxidative stress and can be aggravated by aging, inflammation, and dysregulation of iron homeostasis. In the central nervous system, iron dyshomeostasis, mitochondrial dysfunction, and membrane lipid remodeling can amplify oxidative injury and increase susceptibility to ferroptotic damage, particularly in vulnerable neurons. There is growing evidence that ferroptosis-related processes are linked to Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. This review addresses novel approaches to track ferroptosis in vivo, such as imaging and biomarker techniques, and important molecular mechanisms linking iron metabolism, reactive oxygen species, and PUFA-driven lipid peroxidation to neuronal damage. We also explore upstream transcriptional control via NRF2, iron chelation and iron-handling modulation, inhibition of lipid peroxidation, and reinforcement of the System Xc-GSH-GPX4 and CoQ10-linked defense pathways. Subsequently, we highlight translational issues that need attention to further progress ferroptosis-targeted therapies for neurodegenerative disease.},
}

*Ferroptosis
Humans
*Oxidative Stress
Animals
*Neurodegenerative Diseases/metabolism/pathology
Lipid Peroxidation
Iron/metabolism
Reactive Oxygen Species/metabolism

@article {pmid42074010,
year = {2026},
author = {Goloborshcheva, VV and Kostikova, YS and Kucheryanu, VG and Morozov, SG and Kokhan, VS},
title = {Insights into the Impact of Low-Dose Ionizing Radiation on Neurodegenerative Disease Progression in In Vivo Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083368},
pmid = {42074010},
issn = {1422-0067},
support = {FGFU-2025-0004//Russian state contract/ ; },
mesh = {Animals ; Humans ; *Radiation, Ionizing ; *Neurodegenerative Diseases/radiotherapy/pathology/metabolism ; Disease Models, Animal ; Disease Progression ; Autophagy/radiation effects ; DNA Repair/radiation effects ; },
abstract = {The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored.},
}

Animals
Humans
*Radiation, Ionizing
*Neurodegenerative Diseases/radiotherapy/pathology/metabolism
Disease Models, Animal
Disease Progression
Autophagy/radiation effects
DNA Repair/radiation effects

@article {pmid42074014,
year = {2026},
author = {Li, Y and Ma, S and Fei, T},
title = {CRISPR Applications in Alzheimer's Disease: From High-Throughput Genetic Screening to Precision Editing and CNS Delivery.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083371},
pmid = {42074014},
issn = {1422-0067},
mesh = {*Alzheimer Disease/genetics/therapy ; Humans ; *Gene Editing/methods ; *CRISPR-Cas Systems ; Animals ; Genetic Therapy/methods ; tau Proteins/genetics/metabolism ; *Genetic Testing/methods ; High-Throughput Screening Assays ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {Alzheimer's disease is a devastating progressive neurodegenerative disorder characterized by extracellular amyloid-beta plaques and intracellular tau tangles. Despite recent advancements in amyloid-beta-targeting immunotherapies, achieving safe and definitive disease control remains a profound clinical challenge. The CRISPR/Cas9 system has emerged as a powerful technology for precision neurogenetics, offering significant potential to address the fundamental questions behind Alzheimer's disease. This comprehensive review delineates the trajectory of CRISPR applications in Alzheimer's disease research and therapeutics. First, we explore the integration of CRISPR in engineering high-fidelity in vitro models, such as isogenic induced pluripotent stem cells and three-dimensional cerebral organoids, alongside advanced in vivo mammalian models. Second, we examine how these platforms facilitate unbiased high-throughput genetic screening to uncover molecular underpinnings regulating tau, lipid metabolism, and neuroinflammation. Third, we critically evaluate precision editing strategies targeting core risk genes (APP, MAPT, APOE, and TREM2), explicitly highlighting the severe physiopathological trade-offs between therapeutic efficacy and loss-of-function toxicity. Finally, we address the ultimate translational bottlenecks impeding clinical application. By dissecting the packaging limits of adeno-associated viral vectors and the physical barricade of the blood-brain barrier, we underscore the necessity of transitioning toward next-generation base editors and non-viral lipid nanoparticles to realize safe and efficacious in vivo clinical gene therapies against Alzheimer's disease.},
}

*Alzheimer Disease/genetics/therapy
Humans
*Gene Editing/methods
*CRISPR-Cas Systems
Animals
Genetic Therapy/methods
tau Proteins/genetics/metabolism
*Genetic Testing/methods
High-Throughput Screening Assays
Induced Pluripotent Stem Cells/metabolism

@article {pmid42074073,
year = {2026},
author = {Guix, FX},
title = {Metatranscriptomic Reanalysis of Alzheimer's Brains Identifies Low-Biomass Microbial Signals Including Enrichment of Acinetobacter radioresistens.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083430},
pmid = {42074073},
issn = {1422-0067},
support = {2025-URL-Proj-007//Universitat Ramon Llull/ ; },
mesh = {*Alzheimer Disease/microbiology/genetics/metabolism/pathology ; Humans ; *Acinetobacter/genetics/isolation & purification ; Aged ; *Transcriptome ; Female ; Male ; *Brain/metabolism/microbiology ; Biomass ; Aged, 80 and over ; Microbiota ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Beyond genetic and proteostatic mechanisms, infection- and dysbiosis-based models of AD have gained renewed attention, including the antimicrobial protection hypothesis, in which Aβ may participate in innate immune defense. Here, we reanalyzed ribosomal depleted (Ribo-Zero) RNA-seq data from dorsolateral prefrontal cortex (DLPFC) samples from the Mount Sinai Brain Bank cohort (GSE53697) to screen for non-human transcripts. Reads underwent quality control and adapter trimming, taxonomic classification with Kraken2, abundance re-estimation with Bracken, and differential abundance testing with edgeR. Across 17 samples (9 advanced AD and 8 controls), we detected low-biomass microbial signals, with Acinetobacter radioresistens showing enrichment in the AD group (FDR = 0.018). Several additional taxa showed suggestive group differences but did not remain significant after multiple testing correction, including Lactobacillus iners (FDR = 0.051). We also performed an exploratory in silico analysis of an A. radioresistens biofilm-associated protein homolog, identifying predicted amyloidogenic motifs and surface-exposed regions that may be relevant to cross-seeding hypotheses, although no mechanistic inference can be drawn without experimental validation. Given the technical challenges of inferring microbial signals from post-mortem brain RNA-seq data, including contamination risk, low microbial biomass, and overwhelming host background, these findings should be interpreted as hypothesis-generating and warrant orthogonal validation in larger, microbiome-aware cohorts.},
}

*Alzheimer Disease/microbiology/genetics/metabolism/pathology
Humans
*Acinetobacter/genetics/isolation & purification
Aged
*Transcriptome
Female
Male
*Brain/metabolism/microbiology
Biomass
Aged, 80 and over
Microbiota
Gene Expression Profiling

@article {pmid42074152,
year = {2026},
author = {Wang, W and Zhao, Y and Li, Z and Lv, Y and Xu, Z and Qi, B and Yin, J and Wang, C},
title = {Astragaloside IV Improves Cognitive Impairment in Alzheimer's Mice by Alleviating Neuron PANoptosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083508},
pmid = {42074152},
issn = {1422-0067},
support = {ZD2023C004//Heilongjiang Natural Science Foundation/ ; 32371840 and 82001113//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Saponins/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Triterpenes/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism/pathology ; *Cognitive Dysfunction/drug therapy/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Male ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology ; Pyroptosis/drug effects ; Apoptosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective treatments are currently available. PANoptosis is a coordinated cell death pathway involving pyroptosis, apoptosis, and necroptosis. Astragaloside IV (AS-IV) is a bioactive saponin derived from Astragalus membranaceus. Behavioral performance was evaluated using the Morris water maze and open field tests, while neuronal damage was assessed by Nissl staining. The expression levels of Aβ, IL-18, and PANoptosis-related proteins were analyzed by Western blot. Immunofluorescence was performed to assess the co-localization of PANoptosis-associated proteins with neurons in the hippocampal region. In addition, the effects of AS-IV on the expression of PANoptosis-related proteins were examined in Aβ-induced HT22 cells. AS-IV improved spatial memory performance and alleviated anxiety-like behaviors in AD mice. Furthermore, AS-IV treatment significantly reduced Aβ protein levels and attenuated neuronal loss in the hippocampus. Key markers of PANoptosis were downregulated following AS-IV treatment. Immunofluorescence revealed strong co-localization between PANoptosis-associated proteins and neurons. In vitro, AS-IV also inhibited the Aβ-induced upregulation of PANoptosis-related proteins in HT22 cells. Collectively, these results indicate that AS-IV exerts neuroprotective effects in AD models, which may be associated with reduced Aβ protein deposition, attenuated neuronal loss, and the regulation of PANoptosis-related proteins in the hippocampus.},
}

Animals
*Saponins/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
*Triterpenes/pharmacology/therapeutic use
Mice
*Neurons/drug effects/metabolism/pathology
*Cognitive Dysfunction/drug therapy/metabolism
Hippocampus/drug effects/metabolism/pathology
Male
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Neuroprotective Agents/pharmacology
Pyroptosis/drug effects
Apoptosis/drug effects

@article {pmid42074200,
year = {2026},
author = {Zorkina, Y and Abramova, O and Zubkov, E and Gurina, O and Ushakova, V},
title = {Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083560},
pmid = {42074200},
issn = {1422-0067},
support = {25-75-10063//Russian Science Foundation/ ; },
mesh = {*Alzheimer Disease/diagnosis/therapy/drug therapy/metabolism ; Humans ; *Theranostic Nanomedicine/methods ; Animals ; Amyloid beta-Peptides/metabolism ; *Nanoparticles/chemistry/therapeutic use ; },
abstract = {Alzheimer's disease (AD) remains an incurable neurodegenerative disorder. The concept of theranostics-combining diagnostic and therapeutic functions within a single nanoplatform-has been explored for over a decade. Despite a growing number of publications, no theranostic system has yet reached clinical application for AD. This critical review analyzes the fundamental conceptual contradictions that hinder the clinical translation of theranostic nanoplatforms for AD and identifies alternative strategies where nanotechnology may still be beneficial. The review presents key aspects essential for understanding theranostics challenges: AD molecular targets, analysis of existing nanoplatforms, identification of three inherent conceptual conflicts, and viable alternative approaches. Our analysis reveals three core conceptual conflicts: the pharmacokinetic conflict, where diagnostics demand rapid accumulation and clearance while therapy requires prolonged retention-exacerbated by minimal brain delivery (1-2% ID/g) and peripheral toxicity risks; the dose conflict, characterized by orders-of-magnitude disparities between diagnostic and therapeutic dosing, rarely quantified for identical particles; and the temporal conflict, pitting one-time diagnostics against chronic therapy needs, as long-persisting particles generate irremovable brain background signals. We further identify a pervasive methodological trap: predominant focus on mature β-amyloid (Aβ) fibrils overlooks soluble oligomers as the primary toxic species. We conclude by proposing viable alternatives: preclinical intervention for time-limited "hit-and-clear" applications; coordinated theranostic monitoring with separate diagnostics/therapy; theranostic pairs using ligand-matched, function-optimized particles; and external stimuli for temporal function separation. A practical roadmap guides the transition from conceptual demonstrations to clinical translation. Addressing these contradictions can transform theranostics from elegant chemical constructs into clinically meaningful AD tools.},
}

*Alzheimer Disease/diagnosis/therapy/drug therapy/metabolism
Humans
*Theranostic Nanomedicine/methods
Animals
Amyloid beta-Peptides/metabolism
*Nanoparticles/chemistry/therapeutic use

@article {pmid42074231,
year = {2026},
author = {Wang, X and Harnett, W and Shu, X and Jiang, HR},
title = {Alzheimer's Spinal Pathology: Neuronal, Glial, and Cholesterol Metabolic Changes in Female and Male 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083593},
pmid = {42074231},
issn = {1422-0067},
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism ; Male ; Female ; *Cholesterol/metabolism ; Mice ; *Spinal Cord/pathology/metabolism ; Mice, Transgenic ; *Neuroglia/metabolism/pathology ; *Neurons/metabolism/pathology ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Astrocytes/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain.},
}

Animals
*Alzheimer Disease/pathology/metabolism
Male
Female
*Cholesterol/metabolism
Mice
*Spinal Cord/pathology/metabolism
Mice, Transgenic
*Neuroglia/metabolism/pathology
*Neurons/metabolism/pathology
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Astrocytes/metabolism/pathology

@article {pmid42074275,
year = {2026},
author = {Dias, I and Guerreiro-Oliveira, C and Melo-Marques, I and Cardoso, SM and Guedes, RC and Carvalho, I and Rocha, T and Chavarria, D and Chaves, S and Santos, MA},
title = {Emerging Roles of Rivastigmine Derivatives Bearing Antioxidant Motifs as Multi-Target Agents for the Management of Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083637},
pmid = {42074275},
issn = {1422-0067},
mesh = {*Rivastigmine/pharmacology/chemistry/analogs & derivatives ; *Antioxidants/pharmacology/chemistry ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Cholinesterase Inhibitors/pharmacology/chemistry ; Monoamine Oxidase/metabolism ; Reactive Oxygen Species/metabolism ; Parkinson Disease/drug therapy/metabolism ; },
abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's and Parkinson's diseases (AD and PD), despite having different main neuropathological hallmarks, share several interconnected aetiologic mechanisms and lack effective disease-modifying treatments. The multifactorial nature of these diseases has encouraged the development of new drugs such as multi-target-directed ligands (MTDLs). In this work, an anti-AD drug (rivastigmine, RIV) was fused and conjugated with a series of antioxidant scaffolds to obtain a small library of RIV-antiox hybrids. In addition to inhibitory activity towards both cholinesterases, these hybrids exhibited radical scavenging activity, inhibition of Aβ aggregation, and neuroprotection against cell death induced in AD models. The relevant anti-AD properties already found for these hybrids challenged us to also assess their capacity to modulate and interfere with ROS-associated harmful dysfunctions, namely in the dysregulation of biometal ions (Fe[3+], Cu[2+], and Zn[2+]) and upregulation of monoamine oxidases (MAOs). In particular, the capacity of the hybrids for metal chelation and inhibition of Cu-induced Aβ aggregation and MAO isoforms was evaluated, as well as their neuroprotection capacity in cell models of PD. Overall, some of these RIV hybrids appear as lead compounds for the development of novel multifunctional agents against NDs.},
}

*Rivastigmine/pharmacology/chemistry/analogs & derivatives
*Antioxidants/pharmacology/chemistry
Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry
Amyloid beta-Peptides/metabolism
Alzheimer Disease/drug therapy/metabolism
Animals
Cholinesterase Inhibitors/pharmacology/chemistry
Monoamine Oxidase/metabolism
Reactive Oxygen Species/metabolism
Parkinson Disease/drug therapy/metabolism

@article {pmid42074305,
year = {2026},
author = {Siebner, AS and Uversky, VN},
title = {Amyloid-β, Tau Protein, α-Synuclein, TDP-43, and FUS in Mixed Pathology: And Intrinsic Disorder to Rule Them All.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083669},
pmid = {42074305},
issn = {1422-0067},
support = {CREATE (Collaborative Research Excellence and Translational Efforts) award//University of South Florida/ ; },
mesh = {Humans ; *alpha-Synuclein/metabolism ; *tau Proteins/metabolism ; *RNA-Binding Protein FUS/metabolism ; *DNA-Binding Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Intrinsically Disordered Proteins/metabolism ; Animals ; },
abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Lewy Body Disease (LBD), and related dementias, represent a global health challenge, particularly in aging populations. The simultaneous occurrence of neurodegenerative diseases in an aging population suggests a potential link between causative proteins. Such neurodegenerative proteins, including amyloid-β (Aβ), τ-protein (tau), α-synuclein, TAR DNA-binding protein 43 (TDP-43), and Fused in Sarcoma (FUS), share key characteristics of intrinsically disordered proteins (IDPs), which can explain promiscuous physical interactions, cross-seeding, co-occurrence, pathological synergy, and shared upstream and downstream mechanisms. This review synthesizes current evidence on (1) shared biophysical features of neurodegeneration-associated proteins, (2) mechanisms driving mixed neuropathology, (3) therapeutic implications of disorder-driven interactions, and (4) key unresolved questions shaping future research. By framing neurodegeneration as a network of interacting, disorder-driven proteinopathies rather than isolated entities, this perspective highlights the need for integrative, systems-level approaches to better understand disease heterogeneity and to identify novel targets for intervention.},
}

Humans
*alpha-Synuclein/metabolism
*tau Proteins/metabolism
*RNA-Binding Protein FUS/metabolism
*DNA-Binding Proteins/metabolism
*Amyloid beta-Peptides/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Intrinsically Disordered Proteins/metabolism
Animals

@article {pmid42074330,
year = {2026},
author = {Alsina, R and Riba, M and Sartorio, M and Romera, C and Vilaplana, B and Prats, E and Molina-Porcel, L and Del Valle, J and Pelegrí, C and Vilaplana, J},
title = {Cerebrospinal Fluid Sediments as a Novel Tool for Potential Biomarkers of Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083692},
pmid = {42074330},
issn = {1422-0067},
support = {PID2020-115475GB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2023-148768OA-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2024-159003OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00288 625//Generalitat de Catalunya/ ; CERCA//Generalitat de Catalunya/ ; Formación de Profesorado Universitario (FPU) 2022 fellowship//Ministerio de Ciencia, Innovación y Universidades/ ; Formación de Personal Investigador (FPI) 2022 fellowship//Ministerio de Ciencia, Innovación y Universidades/ ; CEX2021-001159-M//Ministerio de Ciencia, Innovación y Universidades/ ; },
mesh = {*Biomarkers/cerebrospinal fluid ; Humans ; *Neurodegenerative Diseases/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/pathology ; *Supranuclear Palsy, Progressive/cerebrospinal fluid ; Male ; Female ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Brain/metabolism/pathology ; },
abstract = {Cerebrospinal fluid (CSF) biomarkers for neurodegenerative diseases have been extensively studied over the years. However, CSF samples are routinely centrifuged, and the resulting sediment or pellet is typically discarded to remove cellular debris and high-density particles. This standard practice raises a critical question: Could these discarded sediments harbour potential biomarkers? The aim of the present study is to demonstrate that CSF sediments contain specific brain-derived components and thus to substantiate the possible presence of biomarkers within these sediments. To this end, we analysed post-mortem CSF samples of one patient with neuropathologically confirmed Alzheimer's disease (AD) and one patient with confirmed progressive supranuclear palsy (PSP). CSF pellets were studied using transmission and scanning electron microscopy techniques (TEM and SEM, respectively), along with compositional analysis through SEM combined with energy-dispersive X-ray spectroscopy (SEM-EDX), as well as immunofluorescence and histochemical analyses on semithin pellet sections. We observed that, among others, CSF pellets contain brain-derived structures such as wasteosomes and psammoma bodies. Furthermore, we also found disease-relevant proteins, including tau and Aβ42 in the AD sediment and tau in the PSP sediment. Although further studies are required, the study of CSF pellets could open new avenues for biomarker discovery in neurodegenerative diseases.},
}

*Biomarkers/cerebrospinal fluid
Humans
*Neurodegenerative Diseases/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/pathology
*Supranuclear Palsy, Progressive/cerebrospinal fluid
Male
Female
Amyloid beta-Peptides/cerebrospinal fluid
Aged
Brain/metabolism/pathology

@article {pmid42074385,
year = {2026},
author = {Ku, TL and Dillon, K and Karelitz, H and Mortensen, A and VanDenBergh, SC and Edwards, DM and Quarcoo, E and Kuhlman, CM and Gerhardt, MM and Arsenault Knudsen, ÉN and Fields, B},
title = {Barriers and Strategies for Recruiting Care Partners During the Hospitalization of People Living with Dementia: Lessons from a Hospital-Based Randomized Controlled Trial.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {4},
pages = {},
doi = {10.3390/ijerph23040447},
pmid = {42074385},
issn = {1660-4601},
support = {K23AG080068/AG/NIA NIH HHS/United States ; P30-AG062715//Wisconsin Alzheimer's Disease Research Center Grant/ ; },
mesh = {Humans ; *Dementia/therapy ; *Hospitalization ; *Caregivers/psychology ; *Patient Selection ; Male ; Female ; Qualitative Research ; Aged ; },
abstract = {Background: Recruiting care partners (CPs) of hospitalized people living with dementia is challenging due to rapid discharge timelines and complex inpatient workflows. This study identified barriers to CP recruitment encountered during the first year of a hospital-based randomized controlled trial and the strategies implemented in response to them. Methods: A qualitative descriptive study using thematic analysis of twelve study coordination and implementation meeting transcripts was conducted. Recruitment outcomes were examined to assess changes before and after implementation of the enhanced recruitment workflow. Results: Eight recruitment barriers were identified, including fragmented electronic health record (EHR) documentation, uncertainty in CP presence, limited clinician availability, passive study promotion, and inefficient clinical-research team collaboration. Nine strategies were developed and implemented in response to these barriers. The enhanced recruitment workflow was temporally associated with an increase in average monthly enrollment from 0.25 participants (April-July 2024) to 4 participants (August 2024-December 2025). Over the same periods, the cumulative enrollment rate was 3% and 23%, respectively. Conclusions: Care partner recruitment in inpatient settings is highly context-dependent and requires iterative, implementation-informed adaptation. Effective recruitment may be supported by embedding processes into routine inpatient workflows, clarifying recruitment roles, leveraging EHR-supported identification, and maintaining close clinical-research team collaboration to respond to the unpredictable presence of care partners and short discharge windows.},
}

Humans
*Dementia/therapy
*Hospitalization
*Caregivers/psychology
*Patient Selection
Male
Female
Qualitative Research
Aged

@article {pmid42074388,
year = {2026},
author = {Manias, M and Vieira, JVR and Cremonesi, AS},
title = {In Silico Analyses Suggest That Exercise-Induced Irisin-Mediated Neuroprotection Supports Non-Pharmacological Preventive Strategies for Alzheimer's Disease in Public Health.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {4},
pages = {},
doi = {10.3390/ijerph23040449},
pmid = {42074388},
issn = {1660-4601},
mesh = {*Fibronectins/metabolism/chemistry/genetics ; *Alzheimer Disease/prevention & control/epidemiology ; Humans ; Brazil/epidemiology ; *Exercise ; Molecular Docking Simulation ; *Neuroprotection ; Public Health ; Male ; Computer Simulation ; Female ; Aged ; Molecular Dynamics Simulation ; Hospitalization/statistics & numerical data ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and imposes a high economic and social burden on healthcare systems. In Brazil, the consistent increase in costs associated with AD hospitalizations, coupled with the absence of curative therapies and population aging, reinforces the need for low-cost, broadly applicable preventive strategies. This study investigated the role of irisin, a myokine induced by physical activity, in the prevention of AD, integrating epidemiological and bioinformatic analyses. Public data on the nutritional status of the Brazilian population in the early 2000s and on AD hospitalizations approximately 20 years later were analyzed, assessing the temporal association using a lagged Spearman correlation. Additionally, genes associated with AD were analyzed through protein-protein interaction networks and functional enrichment. Structural models of irisin and the integrin αV/β5 receptor were employed in molecular docking and molecular dynamics analyses. Historical data indicated a high prevalence of excess weight in the early 2000s (46.7% ± 4.2% of the adult population) and a strong positive correlation with AD hospitalizations two decades later (ρ = 0.88; p = 0.033). Functional analyses revealed enrichment of pathways related to neurodegeneration, neurotrophins, and neuronal plasticity, involving proteins such as BDNF, AKT, ERK1/2, and CREB. Docking and molecular dynamics indicated a stable interaction of irisin with the αV/β5 receptor, suggesting activation of neuroprotective pathways. The findings reinforce physical exercise as a strategic public health tool for the prevention of AD, providing an epidemiological and molecular basis to reduce the future burden of the disease, thereby shifting the focus of public health policy from treatment to prevention.},
}

*Fibronectins/metabolism/chemistry/genetics
*Alzheimer Disease/prevention & control/epidemiology
Humans
Brazil/epidemiology
*Exercise
Molecular Docking Simulation
*Neuroprotection
Public Health
Male
Computer Simulation
Female
Aged
Molecular Dynamics Simulation
Hospitalization/statistics & numerical data

@article {pmid42074392,
year = {2026},
author = {Raposo, A and Gonçalves, F and Leonido, L and Mendes, L},
title = {Digital Cognitive Rehabilitation Platforms for Older Adults in Portugal: A Systematic Review.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {4},
pages = {},
doi = {10.3390/ijerph23040453},
pmid = {42074392},
issn = {1660-4601},
support = {THCS/0006/2023//European Partnership Joint Transnational Competition Call THCS "Health Care of the Future"/ ; 3599-PPCDTI//Fundação para a Ciência e Tecnologia/ ; THCS/0006/2023//European Partnership on Transforming Health and Care Systems/ ; },
mesh = {Humans ; Portugal ; *Cognitive Dysfunction/rehabilitation ; Aged ; *Alzheimer Disease/rehabilitation ; Cognitive Training ; },
abstract = {Portugal's demographic ageing calls for effective strategies to address mild cognitive impairment (MCI) and Alzheimer's Disease (AD). However, fragmented evidence on digital tools limits their clinical application. This review aimed to map the landscape of validated digital cognitive rehabilitation platforms in Portugal for older adults with MCI and AD and to analyze their effectiveness, usability, and implementation barriers. Following PRISMA 2020 guidelines, seven studies published between 2015 and 2025 were identified from PubMed, Scopus, and ScienceDirect, complemented by manual searches and platform website analysis. Methodological quality, assessed using the Joanna Briggs Institute (JBI) tools, ranged from 69% to 100%. The included studies evaluated platforms such as the Systemic Lisbon Battery (SLB), Digi&Mind, NeuroVRehab.PT, and the Fit4Alz project. Findings indicate improvements in global cognition, executive functioning, and attention. Multimodal interventions combining digital cognitive training and physical exercise produced more consistent cognitive benefits than isolated approaches. Despite initially low digital literacy among older adults, high adherence and motivation were reported, supported by gamification, user-centred design, and cultural adaptation. Although Portuguese digital platforms show strong potential for cognitive rehabilitation, the evidence base is constrained by methodological heterogeneity, small sample sizes, and short intervention durations. Future research should prioritize long-term follow-up and remote monitoring through telerehabilitation.},
}

Humans
Portugal
*Cognitive Dysfunction/rehabilitation
Aged
*Alzheimer Disease/rehabilitation
Cognitive Training

@article {pmid42074686,
year = {2026},
author = {Goldstein, D and Sahelijo, N and Priyadarshi, D and Panitch, R and Nho, K and Farrer, LA and Stein, TD and Jun, GR},
title = {Blood-Brain Network-Based Polygenic Risk Scores Reveal Biomarker Signatures and the Progression of Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/jcm15082885},
pmid = {42074686},
issn = {2077-0383},
support = {R01-AG069453/AG/NIA NIH HHS/United States ; U01-AG068057/AG/NIA NIH HHS/United States ; U01-AG082665/AG/NIA NIH HHS/United States ; U19-AG079774/AG/NIA NIH HHS/United States ; P30-AG072978/AG/NIA NIH HHS/United States ; R01-AG048927/AG/NIA NIH HHS/United States ; U01-AG081230/AG/NIA NIH HHS/United States ; U19-AG068753/AG/NIA NIH HHS/United States ; T32GM100842/GM/NIGMS NIH HHS/United States ; },
abstract = {Background: Polygenic risk scores for Alzheimer's disease (AD), organized by gene networks shared between the blood and brain, may provide insights into underlying disease mechanisms common to both tissues. Methods: We derived a blood-brain network-based polygenic risk score (nbPRS) from AD-associated genetic variants for three blood-brain networks, selected by the preservation of blood and brain gene co-expression networks, and AD association. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1109), Framingham Heart Study (FHS, n = 8310), the Religious Orders Study Memory Aging Project (ROSMAP, n = 1215), and Mount Sinai Brain Bank (MSBB, n = 323) were stratified into low- and high-nbPRS subgroups, then profiled using longitudinal and cross-sectional data. We compared the conversion from normal cognition to AD between nbPRS subgroups. Genes differentially expressed among low- and high-nbPRS individuals were profiled with classical neuropathological markers and we investigated potential biologically relevant pathways for the genes significantly expressed in high-risk individuals. Results: Individuals with high nbPRS in three AD-associated networks (M2, M6, M14) demonstrated significant impairment in executive function and memory performance, whereas high-risk individuals in networks M2 and M14 had significantly reduced hippocampal volume. We observed high-risk individuals in M2 and M14 developed AD at twice the rate of low-risk individuals in these networks. HLA genes were differentially expressed with transcriptome-wide significance among low- and high-nbPRS individuals in M14 and associated with neuroinflammatory and tau pathology. Conclusions: Polygenic risk scores derived from blood and brain networks can differentiate individuals with a high risk of AD conversion.},
}

@article {pmid42074758,
year = {2026},
author = {Tanaka, M and Hidaka, Y and Mori, F},
title = {Neurophysiological Characteristics Associated with Driving Abilities in Older Adults: A Scoping Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/jcm15082956},
pmid = {42074758},
issn = {2077-0383},
abstract = {With population aging, motor vehicle accidents involving older drivers have increased. Age-related cognitive decline affects driving performance; however, the underlying neural mechanisms remain unclear. This scoping review explored neurophysiological characteristics associated with driving in older adults, including those at risk of dementia. Following PRISMA-ScR guidelines, we searched PubMed, Scopus, and CINAHL for studies examining driving-related neurophysiological measures in older adults aged ≥60 years. Twelve studies were included. Findings converge on load-dependent neural compensation failure: older adults maintain driving performance under low-to-moderate demands, but compensatory mechanisms break down under high cognitive load. Electroencephalography (EEG) studies revealed blunted midfrontal theta upregulation during high-load conditions, associated with reduced steering precision and delayed responses. Event-related potential studies demonstrated that reduced P3b amplitude was associated with missed braking responses and that abnormal visual evoked potentials in Alzheimer's disease predicted unfit-to-drive classifications. fNIRS studies during driving-related tasks and an fMRI study using a laboratory-based visual task consistently showed prefrontal hyperactivation in older adults. Although some older adults maintained comparable performance to younger adults, the brain-behavior associations observed in younger adults were absent, suggesting that this hyperactivation does not necessarily serve a functional compensatory role. Combined with EEG evidence of impaired oscillatory modulation, these findings suggest that prefrontal hyperactivation does not necessarily compensate for diminished neural synchronization under high-load conditions. Neurophysiological markers hold promise for fitness-to-drive assessments. Future research should employ high-load scenarios and multimodal neuroimaging to verify prefrontal compensatory mechanisms.},
}

@article {pmid42074823,
year = {2026},
author = {Kim, SJ and Lee, JH and Jang, JW and Choi, M and Suh, IB},
title = {Associations of Circadian Rhythms with Cognitive Performance in Patients with Amnestic Mild Cognitive Impairment (aMCI).},
journal = {Journal of clinical medicine},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/jcm15083023},
pmid = {42074823},
issn = {2077-0383},
support = {2020R1F1A1050416//National Research Foundation of Korea/ ; Clinical Medicine Research Institute (2023)//Chosun University Hospital/ ; },
abstract = {Background/Objectives: Circadian rhythm disruption is linked to cognitive decline, yet it remains unclear how behavioral and physiological rhythm markers are differently associated with cognition in amnestic mild cognitive impairment (aMCI). The primary aim of this study was to compare sleep-wake timing, rest-activity rhythm (RAR), and dim light melatonin onset (DLMO) between patients with aMCI and cognitively normal controls. Exploratory analyses further examined their associations with domain-specific cognitive performance. Methods: Eighteen aMCI patients and 21 cognitively normal controls (NC) enrolled. Cognitive function was assessed using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-K). Participants underwent 5-day actigraphy to assess sleep-wake timing and non-parametric RAR variables, including interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA). DLMO was determined from hourly salivary melatonin samples collected over five hours before sleep onset under dim-light conditions. Group comparisons of circadian markers were conducted as the primary analyses, and generalized linear models were used for exploratory analyses of associations between circadian markers and cognitive outcomes. Results: Groups did not significantly differ in sleep-wake timing, RAR parameters and DLMO. Sleep-wake timing variables and DLMO were not significantly associated with cognitive performance. Higher IS was associated with better visuospatial memory and executive function, whereas higher RA was associated with poorer verbal memory among aMCI patients. Conclusions: Although sleep-wake timing and melatonin phase did not differ between groups nor predict cognitive performance, higher daily rhythm stability was linked to better non-verbal memory and executive functioning. In contrast, high RA may relate to poorer verbal memory in aMCI, suggesting that elevated RA may not reflect true circadian robustness required for optimal cognition.},
}

@article {pmid42074869,
year = {2026},
author = {Carnazzo, SM and Fanos, V},
title = {The Microbiota-Gut-Brain Axis Across the Lifespan: From Neurodevelopment to Neurodegeneration.},
journal = {Journal of clinical medicine},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/jcm15083065},
pmid = {42074869},
issn = {2077-0383},
abstract = {The microbiota-gut-brain axis (MGBA) is a complex bidirectional communication network integrating neural, endocrine, immune, and metabolic pathways linking intestinal microbiota to central nervous system function. Increasing evidence indicates that microbiota-derived signals are critical regulators of neurodevelopment and may contribute to vulnerability to neurodegenerative disorders across the lifespan. In this narrative review, we synthesize experimental and clinical evidence to define the key biological mechanisms underlying microbiota-brain interactions. Converging data indicate that immune activation, barrier dysfunction, and microbial metabolites, particularly short-chain fatty acids and tryptophan-derived compounds, represent central mediators linking gut dysbiosis to neuroinflammatory and neurodegenerative processes. Early-life microbial perturbations, driven by factors such as antibiotic exposure, diet, and psychosocial stress, appear to induce long-term immunometabolic programming that may increase susceptibility to neurological disorders later in life. Clinical studies consistently associate dysbiosis with neurodevelopmental conditions and major neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease; however, causal relationships remain incompletely defined due to heterogeneity and the predominance of observational data. Overall, the available evidence supports a lifespan model in which microbiota-driven immune and metabolic dysregulation contributes to both early neurodevelopmental trajectories and late-life neurodegeneration. While microbiome-based biomarkers and therapeutic strategies show promise, their clinical translation requires validation in longitudinal and interventional studies.},
}

@article {pmid42075071,
year = {2026},
author = {Michel, A and Pourié, G and Kökten, T},
title = {Consequences of Western and Mediterranean Diets' Nutrients on the Microbiota-Gut-Brain Axis.},
journal = {Nutrients},
volume = {18},
number = {8},
pages = {},
doi = {10.3390/nu18081258},
pmid = {42075071},
issn = {2072-6643},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Diet, Mediterranean/adverse effects ; *Brain/physiology ; *Diet, Western/adverse effects ; *Brain-Gut Axis/physiology ; Dysbiosis ; *Nutrients ; *Gastrointestinal Tract/microbiology ; Neurodegenerative Diseases ; },
abstract = {Background: The prevalence of neurodegenerative diseases like Alzheimer's and mental disorders like depression or anxiety appears higher in patients with gastrointestinal tract diseases like inflammatory bowel disease (IBD). Conversely, depressed patients have higher rates of gastrointestinal disorders. These observations suggest bidirectional communication between the brain and the gastrointestinal tract, the so-called "gut-brain axis". Moreover, an altered microbiota, called "dysbiosis", has been reported in these diseases, highlighting the network between gut microbes and their host. The emergence of the microbiota as a key regulator of the gut-brain dialog has led to the establishment of the concept of the "microbiota-gut-brain axis". Objectives: In this narrative review, we outline the main interaction channels between the gastrointestinal tract and the brain. Then, we summarize current knowledge of two major diets (i.e., Western and Mediterranean diets) and the principal dietary components that modulate the microbiota-gut-brain axis to discuss the mechanisms putatively involved in intestinal, psychiatric, and neurological disorders. Conclusions: Diet is a major factor influencing the gut microbiota, and consequently, also putatively systemic mechanisms through the microbiota-gut-brain axis. Indeed, the composition of the diet is crucial for health and disease. Despite the main role of diet, the physiological, cellular, or molecular mechanisms involved in the complex communication between the microbiome, gut, and brain are still poorly understood.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Diet, Mediterranean/adverse effects
*Brain/physiology
*Diet, Western/adverse effects
*Brain-Gut Axis/physiology
Dysbiosis
*Nutrients
*Gastrointestinal Tract/microbiology
Neurodegenerative Diseases

@article {pmid42075076,
year = {2026},
author = {Lawal, R and Kumar, S and Chigevenga, R and Coe, S},
title = {Interactions Between Blood Nutritional Biomarkers and Apolipoprotein E ε4 in the Progression of Mild Cognitive Impairment in Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {8},
pages = {},
doi = {10.3390/nu18081263},
pmid = {42075076},
issn = {2072-6643},
mesh = {Humans ; *Cognitive Dysfunction/blood/genetics ; *Alzheimer Disease/blood/genetics ; *Apolipoprotein E4/genetics/blood ; Biomarkers/blood ; *Nutritional Status ; Aged ; Disease Progression ; Male ; Female ; Middle Aged ; Vitamin D/blood ; Selenium/blood ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND/OBJECTIVES: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer's disease, may be influenced by nutritional status and genetic susceptibility. This systematic review synthesised evidence on how nutritional biomarkers interact with genetic variants, particularly APOE ε4, to influence cognitive outcomes in individuals with MCI.

METHODS: Following PRISMA 2020 guidelines, seven studies were included (three longitudinal, two randomised controlled trials, and two cross-sectional) involving adults aged ≥55 years with MCI. Nutritional exposures comprised plasma or serum concentrations of vitamins A, D, E, the vitamin B group, lipids, selenium, and ketogenic medium-chain triglycerides. Genetic risk was assessed primarily through APOE ε4 status. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence using GRADE. Due to heterogeneity in biomarkers, cognitive tools, and study designs, findings were synthesised narratively.

RESULTS: Across nutrient categories, higher concentrations of vitamin D, selenium, and antioxidants were associated with better cognitive outcomes. kMCT supplementation improved episodic memory and brain energy metabolism. Evidence for nutrient-gene interactions was mixed: APOE ε4 modified responses to vitamin B group and selenium but showed limited influence on vitamin D, lipids, or kMCT effects. Heterogeneity in biomarker assays, cognitive tools, and genetic stratification limited comparability across studies.

CONCLUSIONS: Nutritional biomarkers appear to influence cognitive trajectories in MCI, and some associations may differ by APOE ε4 status. However, small samples and limited genetic stratification constrain interpretation. Future research should prioritise standardised biomarker measurement, genetically stratified cohorts, and individual participant data meta-analyses to clarify nutrient-gene interactions in MCI.},
}

Humans
*Cognitive Dysfunction/blood/genetics
*Alzheimer Disease/blood/genetics
*Apolipoprotein E4/genetics/blood
Biomarkers/blood
*Nutritional Status
Aged
Disease Progression
Male
Female
Middle Aged
Vitamin D/blood
Selenium/blood
Genetic Predisposition to Disease

@article {pmid42075112,
year = {2026},
author = {Hemmati, S and Mohagheghzadeh, A},
title = {The NeuroImmunoEndocrine Circuit of Umami Peptides: A Systems Biology Approach.},
journal = {Nutrients},
volume = {18},
number = {8},
pages = {},
doi = {10.3390/nu18081299},
pmid = {42075112},
issn = {2072-6643},
support = {34561//Shiraz University of Medical Sciences/ ; },
mesh = {Humans ; *Taste/physiology ; *Systems Biology/methods ; Molecular Docking Simulation ; *Peptides/pharmacology/metabolism ; Signal Transduction ; Animals ; Receptors, G-Protein-Coupled/metabolism ; Glucagon-Like Peptide 1/metabolism ; *Neuroimmunomodulation ; },
abstract = {Background/Objectives: Umami peptides enhance flavor and contribute to appetite regulation (satiety) and metabolic health. By signaling to the orbitofrontal cortex, umami has been shown to improve cognitive function in Alzheimer's disease dementia. This taste boosts the immune system and induces saliva secretion. However, the molecular mechanisms linking umami peptides to systemic physiology remain poorly understood. This study provides the first integrated analysis of neurological, immunological, and endocrinological pathways activated by umami peptides. Methods: Novel umami peptides were identified using machine-learning and deep-learning analyses from a library of marine-derived bioactive peptides. T1R1-T1R3 heterodimer is the dominant receptor for umami taste transmission in humans, expressed on taste cells, intestinal cells, and hypothalamic tanycytes. Molecular docking confirmed the binding of novel ligands to the T1R1-T1R3 receptor complex. New candidates and experimentally validated umami peptides, identified by sensomics approaches from tauco, chicken soup, pufferfish, and dry-cured ham, were analyzed using gene ontology. Results: The functional enrichment analysis revealed crosstalk among key signaling processes, including glutamatergic and opioidergic pathways. In addition to the role of µ1 opioid receptor (OPRM1), hub gene intersections highlight cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and the anorexigenic pro-opiomelanocortin (POMC) neurons as potential regulators of the gut-brain axis in satiety signaling. Chemokine-encoding genes, melanin-concentrating hormone (MCH), oxytocin (OXT), and neurotensin (NTS) were other key target genes. Conclusions: The identified targets reveal the coordinated crosstalk between peripheral and central umami signaling that may contribute to the regulation of feeding behavior, satiety, cognition, memory, learning, and immune function. These network-based insights generate hypotheses and guide the design of nutritional and drug-like effectors for metabolic and cognitive health.},
}

Humans
*Taste/physiology
*Systems Biology/methods
Molecular Docking Simulation
*Peptides/pharmacology/metabolism
Signal Transduction
Animals
Receptors, G-Protein-Coupled/metabolism
Glucagon-Like Peptide 1/metabolism
*Neuroimmunomodulation

@article {pmid42075360,
year = {2026},
author = {Pavarino, M and Cagliero, C and Marengo, A and Bicchi, C and Chaves, FCM and Rubiolo, P and Bizzo, HR and Sgorbini, B},
title = {Linking Chemical Profile to Enzyme Inhibition: A Comprehensive Bio-Guided Study of Lippia origanoides Kunth Essential Oil.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/plants15081158},
pmid = {42075360},
issn = {2223-7747},
abstract = {Lippia origanoides Kunth (Verbenaceae family), popularly known in northern Brazil as "Salva-de-Marajó", is a native plant widely used in traditional medicine and cooking. While previous studies have addressed its antimicrobial and insecticidal properties, its ability to inhibit disease-related enzymes has received limited attention. This study investigated the essential oil (EO) of L. origanoides as a source of enzyme inhibitors relevant to Alzheimer's disease, metabolic disorders and skin pigmentation disorders. The EO showed strong inhibitory activity against acetylcholinesterase (IC50: 22.9 μg/mL) and α-glucosidase (IC50: 14.6 μg/mL), indicating potential for managing neurodegenerative conditions and diabetes, respectively. Moderate inhibition was observed for lipase, butyrylcholinesterase and tyrosinase. Although carvacrol, the major EO constituent, contributed significantly to these effects, it did not fully explain the observed bioactivity. Bio-guided fractionation revealed that oxygenated compounds were mainly responsible for inhibiting cholinesterases and lipase, whereas α-glucosidase inhibition was associated with hydrocarbon compounds. Both fractions contributed to tyrosinase inhibition, reinforcing the EO's relevance for treating hyperpigmentation. Furthermore, the EO demonstrated strong antioxidant activity, largely linked to carvacrol and oxygenated constituents. Chemical characterization by GC-MS, GC-FID and enantiomeric analysis strengthened the relationship between composition and bioactivity. Overall, L. origanoides EO emerged as a promising multifunctional natural product for therapeutic and cosmetic applications.},
}

@article {pmid42075568,
year = {2026},
author = {González-Cidad, A and García-Moncó, JC and Román, GC},
title = {Beneficial Effects of Olive Oil and the Mediterranean Diet on Alzheimer's Disease and Vascular Dementia: A Review.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {4},
pages = {},
doi = {10.3390/medicina62040696},
pmid = {42075568},
issn = {1648-9144},
mesh = {Humans ; *Diet, Mediterranean ; *Olive Oil/therapeutic use/pharmacology ; *Alzheimer Disease/diet therapy/prevention & control ; *Dementia, Vascular/diet therapy/prevention & control ; Risk Factors ; Diabetes Mellitus, Type 2/diet therapy ; },
abstract = {Background and Objectives: During the past 25 years, a significant body of research has been conducted reporting on the salutary effects of the Mediterranean diet and extra-virgin olive oil, one of its main components. The initial studies were epidemiological observations on populations with very low mortality rates due to significant reductions in myocardial infarction fatalities. Population-based studies demonstrated that the Mediterranean diet with olive oil consumption is associated with a lower prevalence of cardiovascular and cerebrovascular disease, obesity, arthritis, and cancer. Materials and Methods: In this narrative review, we present recent studies on the effects of extra-virgin olive oil and the Mediterranean diet-compared with various other diets-on several vascular risk factors, including hypertension, hyperlipidemia, type 2 diabetes mellitus, and obesity, as well as their impact on cognitive decline and dementia. Results: This diet has been shown to improve cognitive function in patients with mild cognitive impairment, Alzheimer's disease, vascular cognitive impairment, and vascular dementia. The main mechanisms responsible for cognitive improvement include control of arterial hypertension by reducing systolic and diastolic blood pressure, lowering triglycerides and low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol, along with improvement in fasting glucose, insulin levels, and hemoglobin A1c in subjects with type 2 diabetes mellitus, as well as lowering body mass index and obesity. Conclusions: The Mediterranean diet and olive oil induce-along with prevention of cardiovascular disease and stroke-a significant improvement of vascular risk factors, slowing the progression of both vascular dementia and Alzheimer's disease. There is a need for additional placebo-controlled clinical trials to confirm the supportive nutritional role of extra-virgin olive oil in age-associated cognitive decline in the elderly.},
}

Humans
*Diet, Mediterranean
*Olive Oil/therapeutic use/pharmacology
*Alzheimer Disease/diet therapy/prevention & control
*Dementia, Vascular/diet therapy/prevention & control
Risk Factors
Diabetes Mellitus, Type 2/diet therapy

@article {pmid42075749,
year = {2026},
author = {Stacey, SP and Mounce, BC},
title = {Polyamines as Gatekeepers of Virus Replication and Central Nervous System Homeostasis.},
journal = {Pathogens (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/pathogens15040422},
pmid = {42075749},
issn = {2076-0817},
support = {R35GM138199/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Polyamines/metabolism ; *Homeostasis ; *Virus Replication/physiology ; *Central Nervous System/virology/metabolism ; Animals ; },
abstract = {Polyamines are small, positively charged molecules essential for fundamental cellular processes, including transcription, translation, and membrane fluidity. In the central nervous system (CNS), these molecules serve as homeostatic gatekeepers by modulating neuroreceptors like NMDA and supporting autophagic clearance. While basal polyamine levels are necessary for proper neuronal differentiation and memory formation, their dysregulation is a hallmark of neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases. Neurotropic viruses, including poliovirus, Zika virus, and human cytomegalovirus are significant human pathogens that rely on cellular metabolites for their replication, including polyamines. These pathogens exploit polyamines at multiple stages of their life cycles, relying on them for virion stability, cellular attachment, and the stimulation of viral enzyme activity. Notably, diverse viral families share this dependence, making polyamine biosynthesis a prime target for broad-spectrum antiviral therapies. This review covers the current understanding of polyamine metabolism in virus infection and CNS health and disease, as well as considering antiviral therapies targeting host polyamines to limit neurotropic virus infection.},
}

Humans
*Polyamines/metabolism
*Homeostasis
*Virus Replication/physiology
*Central Nervous System/virology/metabolism
Animals

@article {pmid42075835,
year = {2026},
author = {Zedde, M and Losa, M and Donniaquio, A and Gandoglia, I and Sette, MD and Roccatagliata, L and Piazza, F and Pardini, M and Pascarella, R},
title = {Drug-Induced Amyloid-Related Imaging Abnormalities: A Neurovascular Perspective on Risk Assessment.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {4},
pages = {},
doi = {10.3390/ph19040579},
pmid = {42075835},
issn = {1424-8247},
abstract = {BACKGROUND: Anti-amyloid therapies (AAT) are reshaping the therapeutic landscape of Alzheimer's disease (AD), yet their implementation remains constrained by the risk of amyloid-related imaging abnormalities (ARIA). Although the ARIA phenomenon is well recognized, most available evidence stems from clinical trial safety reports framed predominantly from a dementia-oriented perspective, with relatively limited integration of vascular neurology principles.

METHODS: In this narrative review, we examine drug-induced ARIA through a neurovascular lens, highlighting how cerebrovascular comorbidity, particularly cerebral amyloid angiopathy (CAA), influences the risk and severity of ARIA.

RESULTS: We critically evaluated how CAA comorbidity has been assessed in randomized controlled trials, focusing on exclusion criteria, imaging thresholds, and the resulting implications for external validity. Finally, we evaluated current approaches to ARIA risk stratification and proposed a more integrative framework that combines vascular imaging markers, APOE ε4 genotype, and key clinical comorbidities.

CONCLUSIONS: A more tailored patient selection and monitoring strategies may ultimately improve real-world outcomes and optimize resources in the era of AAT.},
}

@article {pmid42075881,
year = {2026},
author = {Costachescu, I and Stanciu, GD and Gogu, RM and Tamba, BI},
title = {Targeting Pain and Depression in Alzheimer's Disease: Translational Insights and Emerging Treatments.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {4},
pages = {},
doi = {10.3390/ph19040626},
pmid = {42075881},
issn = {1424-8247},
support = {PN-IV-P2-2.1-TE-2023-0879//This research was funded by a grant of the Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; },
abstract = {Alzheimer's disease (AD) is primarily recognized for progressive cognitive decline driven by beta-amyloid accumulation and tau pathology. However, many individuals with AD also experience chronic pain and depressive symptoms, which significantly impair daily functioning and quality of life and increase caregiver burden. These non-cognitive features are frequently underrecognized, despite evidence suggesting they share overlapping biological pathways with neurodegeneration. Emerging data highlight the role of neuroinflammation, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation, and endocannabinoid system alterations in linking AD pathology to disturbances in pain processing and mood regulation. Persistent microglial activation, cytokine imbalance, redox disruption, and chronic stress signaling may simultaneously promote neuronal vulnerability while shaping affective and nociceptive responses. This review synthesizes current preclinical and clinical evidence on the interplay between pain, depression, and AD, emphasizing their shared pathophysiological mechanisms and clinical relevance. Recognizing these symptoms as integral components of disease progression, rather than isolated comorbidities, can inform the development of integrated, multidimensional therapeutic strategies in AD care.},
}